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Qu L, Sun K, Jiang Z, Wang T, Chen L, Shen C, Gu R. Mechanism investigation of highly selective inhibitors toward phosphodiesterase 5 and 6 via the in vitro calculation and simulation. Front Chem 2024; 12:1400886. [PMID: 39176072 PMCID: PMC11338870 DOI: 10.3389/fchem.2024.1400886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 06/21/2024] [Indexed: 08/24/2024] Open
Abstract
Introduction: In clinical practice, phosphodiesterase 5 (PDE5) inhibitors are commonly used to treat erectile dysfunction and pulmonary arterial hypertension. However, due to the high structural similarity between PDE5 and Phosphodiesterase 6 (PDE6), there is a risk that existing drugs will cause off-target effects on PDE6 resulting in visual disorders such as low visual acuity and color blindness. Previous research on the selectivity of PDE5 inhibitors focused on marketed drugs such as sildenafil and tadalafil. Methods: In this study, a highly selective PDE5 inhibitor, ligand3, was used as the subject, and molecular docking, molecular dynamics simulations, MM-GBSA, alanine scanning, and independent gradient model analysis were employed to investigate the biological mechanism underlying the selectivity of PDE5 inhibitors. Results and Discussion: The present work revealed that the binding mode of ligand3 to the PDE5A and PDE6C targets was distinctly different. Ligand3 exhibited stronger coulombic forces when binding to PDE5A, while showing stronger van der waals forces when binding to PDE6C. Ligand3 binds more deeply at the active site of PDE5A than at PDE6C, allowing its side chains to effectively bind to the critical TYR612, whereas in the case of the shallow binding to PDE6C, ligand3 lacks a similar effect. Mechanism investigations of highly selective inhibitors through computational simulation might provide an insight into potent treatment of drugs.
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Affiliation(s)
- Lihang Qu
- The 4th People’s Hospital of Shenyang, China Medical University, Shenyang, Liaoning, China
| | - Kaijian Sun
- The 4th People’s Hospital of Shenyang, China Medical University, Shenyang, Liaoning, China
| | - Zhouyu Jiang
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, China
| | - Ting Wang
- The 4th People’s Hospital of Shenyang, China Medical University, Shenyang, Liaoning, China
| | - Linlin Chen
- The 4th People’s Hospital of Shenyang, China Medical University, Shenyang, Liaoning, China
| | - Chunjian Shen
- The 4th People’s Hospital of Shenyang, China Medical University, Shenyang, Liaoning, China
| | - Ruidong Gu
- The 4th People’s Hospital of Shenyang, China Medical University, Shenyang, Liaoning, China
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2
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Xing Y, Hou Y, Fan T, Gao R, Feng X, Li B, Pang J, Guo W, Shu T, Li J, Yang J, Mao Q, Luo Y, Qi X, Yang P, Liang C, Zhao H, Chen W, Wang J, Wang C. Endothelial phosphodiesterase 4B inactivation ameliorates endothelial-to-mesenchymal transition and pulmonary hypertension. Acta Pharm Sin B 2024; 14:1726-1741. [PMID: 38572107 PMCID: PMC10985131 DOI: 10.1016/j.apsb.2024.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 12/13/2023] [Accepted: 01/05/2024] [Indexed: 04/05/2024] Open
Abstract
Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A-D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH; however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA-CREB-BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.
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Affiliation(s)
- Yanjiang Xing
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
- Haihe Laboratory of Cell Ecosystem, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300051, China
| | - Yangfeng Hou
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Tianfei Fan
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610044, China
| | - Ran Gao
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Xiaohang Feng
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Bolun Li
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Junling Pang
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Wenjun Guo
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Ting Shu
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
- Haihe Laboratory of Cell Ecosystem, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300051, China
| | - Jinqiu Li
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Jie Yang
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Qilong Mao
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Ya Luo
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Xianmei Qi
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Peiran Yang
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Chaoyang Liang
- Department of Lung Transplantation, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China–Japan Friendship Hospital, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing 100029, China
| | - Hongmei Zhao
- The State Key Laboratory of Complex, Severe, and Rare Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Pathophysiology, Peking Union Medical College, Beijing 100005, China
| | - Wenhui Chen
- Department of Lung Transplantation, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China–Japan Friendship Hospital, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing 100029, China
| | - Jing Wang
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
- Haihe Laboratory of Cell Ecosystem, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300051, China
| | - Chen Wang
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
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3
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Fu Q, Wang Y, Yan C, Xiang YK. Phosphodiesterase in heart and vessels: from physiology to diseases. Physiol Rev 2024; 104:765-834. [PMID: 37971403 PMCID: PMC11281825 DOI: 10.1152/physrev.00015.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 10/17/2023] [Accepted: 11/08/2023] [Indexed: 11/19/2023] Open
Abstract
Phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyze cyclic nucleotides, including cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both cyclic nucleotides are critical secondary messengers in the neurohormonal regulation in the cardiovascular system. PDEs precisely control spatiotemporal subcellular distribution of cyclic nucleotides in a cell- and tissue-specific manner, playing critical roles in physiological responses to hormone stimulation in the heart and vessels. Dysregulation of PDEs has been linked to the development of several cardiovascular diseases, such as hypertension, aneurysm, atherosclerosis, arrhythmia, and heart failure. Targeting these enzymes has been proven effective in treating cardiovascular diseases and is an attractive and promising strategy for the development of new drugs. In this review, we discuss the current understanding of the complex regulation of PDE isoforms in cardiovascular function, highlighting the divergent and even opposing roles of PDE isoforms in different pathogenesis.
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Affiliation(s)
- Qin Fu
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- The Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
| | - Ying Wang
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Chen Yan
- Aab Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, New York, United States
| | - Yang K Xiang
- Department of Pharmacology, University of California at Davis, Davis, California, United States
- Department of Veterans Affairs Northern California Healthcare System, Mather, California, United States
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4
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ElHady AK, El-Gamil DS, Abdel-Halim M, Abadi AH. Advancements in Phosphodiesterase 5 Inhibitors: Unveiling Present and Future Perspectives. Pharmaceuticals (Basel) 2023; 16:1266. [PMID: 37765073 PMCID: PMC10536424 DOI: 10.3390/ph16091266] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/25/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
Phosphodiesterase 5 (PDE5) inhibitors presented themselves as important players in the nitric oxide/cGMP pathway, thus exerting a profound impact on various physiological and pathological processes. Beyond their well-known efficacy in treating male erectile dysfunction (ED) and pulmonary arterial hypertension (PAH), a plethora of studies have unveiled their significance in the treatment of a myriad of other diseases, including cognitive functions, heart failure, multiple drug resistance in cancer therapy, immune diseases, systemic sclerosis and others. This comprehensive review aims to provide an updated assessment of the crucial role played by PDE5 inhibitors (PDE5-Is) as disease-modifying agents taking their limiting side effects into consideration. From a medicinal chemistry and drug discovery perspective, the published PDE5-Is over the last 10 years and their binding characteristics are systemically discussed, and advancement in properties is exposed. A persistent challenge encountered with these agents lies in their limited isozyme selectivity; considering this obstacle, this review also highlights the breakthrough development of the recently reported PDE5 allosteric inhibitors, which exhibit an unparalleled level of selectivity that was rarely achievable by competitive inhibitors. The implications and potential impact of these novel allosteric inhibitors are meticulously explored. Additionally, the concept of multi-targeted ligands is critically evaluated in relation to PDE5-Is by inspecting the broader spectrum of their molecular interactions and effects. The objective of this review is to provide insight into the design of potent, selective PDE5-Is and an overview of their biological function, limitations, challenges, therapeutic potentials, undergoing clinical trials, future prospects and emerging uses, thus guiding upcoming endeavors in both academia and industry within this domain.
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Affiliation(s)
- Ahmed K. ElHady
- School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, New Administrative Capital, Cairo 11865, Egypt;
| | - Dalia S. El-Gamil
- Department of Chemistry, Faculty of Pharmacy, Ahram Canadian University, Cairo 12451, Egypt;
| | - Mohammad Abdel-Halim
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt;
| | - Ashraf H. Abadi
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt;
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5
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Roy S, Kloner RA, Salloum FN, Jovin IS. Cardiac Effects of Phosphodiesterase-5 Inhibitors: Efficacy and Safety. Cardiovasc Drugs Ther 2023; 37:793-806. [PMID: 34652581 PMCID: PMC9010479 DOI: 10.1007/s10557-021-07275-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/01/2021] [Indexed: 01/23/2023]
Abstract
The coexistence of cardiovascular disease and erectile dysfunction is widespread, possibly owing to underlying endothelial dysfunction in both diseases. Millions of patients with cardiovascular disease are prescribed phosphodiesterase-5 (PDE5) inhibitors for the management of erectile dysfunction. Although the role of PDE5 inhibitors in erectile dysfunction therapy is well established, their effects on the cardiovascular system are unclear. Preclinical studies investigating the effect of PDE5 inhibitors on ischemia-reperfusion injury, pressure overload-induced hypertrophy, and chemotoxicity suggested a possible clinical role for each of these medications; however, attempts to translate these findings to the bedside have resulted in mixed outcomes. In this review, we explore the biologic preclinical effects of PDE5 inhibitors in mediating cardioprotection. We then examine clinical trials investigating PDE5 inhibition in patients with heart failure, coronary artery disease, and ventricular arrhythmias and discuss why the studies likely have yet to show positive results and efficacy with PDE5 inhibition despite no safety concerns.
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Affiliation(s)
- Sumon Roy
- Pauley Heart Center, Virginia Commonwealth University Medical Center, McGuire VAMC, 1201 Broad Rock Boulevard, 111J, Richmond, VA, 23249, USA
| | - Robert A Kloner
- Huntington Medical Research Institute, Pasadena, CA, USA
- Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Fadi N Salloum
- Pauley Heart Center, Virginia Commonwealth University Medical Center, McGuire VAMC, 1201 Broad Rock Boulevard, 111J, Richmond, VA, 23249, USA
| | - Ion S Jovin
- Pauley Heart Center, Virginia Commonwealth University Medical Center, McGuire VAMC, 1201 Broad Rock Boulevard, 111J, Richmond, VA, 23249, USA.
- McGuire Veterans Affairs Medical Center, Richmond, VA, USA.
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6
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Ma Y, Zhang F, Zhong Y, Huang Y, Yixizhuoma, Jia Q, Zhang S. A label-free LC/MS-based enzymatic activity assay for the detection of PDE5A inhibitors. Front Chem 2023; 11:1097027. [PMID: 36860644 PMCID: PMC9968969 DOI: 10.3389/fchem.2023.1097027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Accepted: 01/30/2023] [Indexed: 02/15/2023] Open
Abstract
Phosphodiesterase type 5 (PDE5), a cyclic nucleotide phosphodiesterase, controls the duration of the cyclic guanosine monophosphate (cGMP) signal by hydrolyzing cGMP to GMP. Inhibiting the activity of PDE5A has proven to be an effective strategy for treating pulmonary arterial hypertension and erectile dysfunction. Current enzymatic activity assay methods for PDE5A mainly use fluorescent or isotope-labeled substrates, which are expensive and inconvenient. Here, we developed an LC/MS-based enzymatic activity assay for PDE5A without labeling, which detects the enzymatic activity of PDE5A by quantifying the substrate cGMP and product GMP at a concentration of 100 nM. The accuracy of this method was verified by a fluorescently labeled substrate. Moreover, a new inhibitor of PDE5A was identified by this method and virtual screening. It inhibited PDE5A with an IC50 value of 870 nM. Overall, the proposed strategy provides a new method for screening PDE5A inhibitors.
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Affiliation(s)
- Yufeng Ma
- State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, China,Department of Pharmacy, Medical College of Qinghai University, Xining, China
| | - Fengsen Zhang
- State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, China,Department of Pharmacy, Medical College of Qinghai University, Xining, China
| | - Yijing Zhong
- Department of Pharmacy, Medical College of Qinghai University, Xining, China
| | - Yongchun Huang
- Department of Pharmacy, Medical College of Qinghai University, Xining, China
| | - Yixizhuoma
- State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, China
| | - Qiangqiang Jia
- State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, China,*Correspondence: Qiangqiang Jia, ; Shoude Zhang,
| | - Shoude Zhang
- State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, China,Department of Pharmacy, Medical College of Qinghai University, Xining, China,*Correspondence: Qiangqiang Jia, ; Shoude Zhang,
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7
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Chen Z, Huang Y, Cao D, Qiu S, Chen B, Li J, Bao Y, Wei Q, Han P, Liu L. Function of sildenafil on diseases other than urogenital system: An umbrella review. Front Pharmacol 2023; 14:1033492. [PMID: 36814496 PMCID: PMC9939646 DOI: 10.3389/fphar.2023.1033492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 01/16/2023] [Indexed: 02/09/2023] Open
Abstract
Background: To investigate the function of sildenafil on diseases other than urogenital system, an umbrella review was conducted. Methods: Meta-analysis and systematic reviews on this topic were comprehensively evaluated in this umbrella review. Quality of evidence was evaluated through AMSTAR and the Grading of Recommendations, Assessment, Development and Evaluation system to generate a reliable and valid conclusion. Results: 77 out of 1164 meta-analysis were enrolled. 33 significant outcomes and 41 non-significant outcomes were extracted from all eligible articles. We found sildenafil did significant help in reducing arterial systolic pressure, mean pulmonary arterial pressure, pulmonary arterial pressure, systolic pulmonary arterial pressure in patients with pulmonary and cardiovascular diseases. Besides, sildenafil also improved exercise capacity or performance in patients with pulmonary and cardiovascular diseases. Other than these patients, this drug contributed great help in pregnant women with fetal growth restriction and preeclampsia by increasing the weight of newborns and lowering uterine and umbilical pulsatility indices. Additionally, it was reported that utilization of sildenafil has brought increased risk of melanoma. Conclusion: We can conclude from our study that sildenafil played an important role in many fields, especially in vascular protection. This finding provides a strong evidence for further expansion of sildenafil utilization in other diseases.
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Affiliation(s)
- Zeyu Chen
- Department of Urology and Institute of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China,West China School of Clinical Medicine, Sichuan University, Chengdu, China
| | - Yin Huang
- Department of Urology and Institute of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China,West China School of Clinical Medicine, Sichuan University, Chengdu, China
| | - Dehong Cao
- Department of Urology and Institute of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Shi Qiu
- Department of Urology and Institute of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Bo Chen
- Department of Urology and Institute of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China,West China School of Clinical Medicine, Sichuan University, Chengdu, China
| | - Jin Li
- Department of Urology and Institute of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China,West China School of Clinical Medicine, Sichuan University, Chengdu, China
| | - Yige Bao
- Department of Urology and Institute of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Qiang Wei
- Department of Urology and Institute of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Ping Han
- Department of Urology and Institute of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China,*Correspondence: Ping Han, ; Liangren Liu,
| | - Liangren Liu
- Department of Urology and Institute of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China,*Correspondence: Ping Han, ; Liangren Liu,
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Samidurai A, Xi L, Das A, Kukreja RC. Beyond Erectile Dysfunction: cGMP-Specific Phosphodiesterase 5 Inhibitors for Other Clinical Disorders. Annu Rev Pharmacol Toxicol 2023; 63:585-615. [PMID: 36206989 DOI: 10.1146/annurev-pharmtox-040122-034745] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Cyclic guanosine monophosphate (cGMP), an important intracellular second messenger, mediates cellular functional responses in all vital organs. Phosphodiesterase 5 (PDE5) is one of the 11 members of the cyclic nucleotide phosphodiesterase (PDE) family that specifically targets cGMP generated by nitric oxide-driven activation of the soluble guanylyl cyclase. PDE5 inhibitors, including sildenafil and tadalafil, are widely used for the treatment of erectile dysfunction, pulmonary arterial hypertension, and certain urological disorders. Preclinical studies have shown promising effects of PDE5 inhibitors in the treatment of myocardial infarction, cardiac hypertrophy, heart failure, cancer and anticancer-drug-associated cardiotoxicity, diabetes, Duchenne muscular dystrophy, Alzheimer's disease, and other aging-related conditions. Many clinical trials with PDE5 inhibitors have focused on the potential cardiovascular, anticancer, and neurological benefits. In this review, we provide an overview of the current state of knowledge on PDE5 inhibitors and their potential therapeutic indications for various clinical disorders beyond erectile dysfunction.
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Affiliation(s)
- Arun Samidurai
- Division of Cardiology, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia, USA;
| | - Lei Xi
- Division of Cardiology, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia, USA;
| | - Anindita Das
- Division of Cardiology, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia, USA;
| | - Rakesh C Kukreja
- Division of Cardiology, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia, USA;
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9
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Verheyen M, Puschkarow M, Gnipp S, Koesling D, Peters M, Mergia E. The differential roles of the two NO-GC isoforms in adjusting airway reactivity. Am J Physiol Lung Cell Mol Physiol 2022; 323:L450-L463. [PMID: 35972838 PMCID: PMC9529264 DOI: 10.1152/ajplung.00404.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
The enzyme, nitric oxide-sensitive guanylyl cyclase (NO-GC), is activated by binding NO to its prosthetic heme group and catalyzes the formation of cGMP. The NO-GC is primarily known to mediate vascular smooth muscle relaxation in the lung, and inhaled NO has been successfully used as a selective pulmonary vasodilator. In comparison, NO-GC’s impact on the regulation of airway tone is less acknowledged and, most importantly, little is known about the issue that NO-GC signaling is accomplished by two isoforms: NO-GC1 and NO-GC2, implying the existence of distinct “cGMP pools.” Herein, we investigated the functional role of the NO-GC isoforms in respiration by measuring lung function parameters of isoform-specific knockout (KO) mice using noninvasive and invasive techniques. Our data revealed the participation and ongoing influence of NO-GC1-derived cGMP in the regulation of airway tone by showing that respiratory resistance was enhanced in NO-GC1-KOs and increased more pronouncedly after the challenge with the bronchoconstrictor methacholine. The tissue resistance and stiffness of NO-GC1-KOs were also higher because of narrowed airways that cause tissue distortion. Contrariwise, NO-GC2-KOs displayed reduced tissue elasticity, elastic recoil, and airway reactivity to methacholine, which did not even increase in an ovalbumin model of asthma that induced hyperresponsiveness in NO-GC1-KOs. In addition, conscious NO-GC2-KOs showed a higher breathing rate with a shorter duration of inspiration and expiration time, which remained faster even in the presence of bronchoconstrictors that slow down breathing. Thus, we provide evidence of two distinct NO/cGMP pathways in airways, accomplished by either NO-GC1 or NO-GC2, adjusting differentially the airway reactivity.
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Affiliation(s)
- Malte Verheyen
- Institute of Pharmacology and Toxicology, Ruhr University Bochum, Bochum, Germany
| | - Michelle Puschkarow
- Department of Experimental Pneumology, Ruhr University Bochum, Bochum, NRW, Germany
| | - Stefanie Gnipp
- Department of Experimental Pneumology, Ruhr University Bochum, Bochum, NRW, Germany
| | - Doris Koesling
- Institute of Pharmacology and Toxicology, Ruhr University Bochum, Bochum, Germany
| | - Marcus Peters
- Department of Molecular Immunology, Ruhr University Bochum, Bochum, NRW, Germany
| | - Evanthia Mergia
- Institute of Pharmacology and Toxicology, Ruhr University Bochum, Bochum, Germany
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10
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Santos-Gomes J, Gandra I, Adão R, Perros F, Brás-Silva C. An Overview of Circulating Pulmonary Arterial Hypertension Biomarkers. Front Cardiovasc Med 2022; 9:924873. [PMID: 35911521 PMCID: PMC9333554 DOI: 10.3389/fcvm.2022.924873] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/21/2022] [Indexed: 11/16/2022] Open
Abstract
Pulmonary arterial hypertension (PAH), also known as Group 1 Pulmonary Hypertension (PH), is a PH subset characterized by pulmonary vascular remodeling and pulmonary arterial obstruction. PAH has an estimated incidence of 15-50 people per million in the United States and Europe, and is associated with high mortality and morbidity, with patients' survival time after diagnosis being only 2.8 years. According to current guidelines, right heart catheterization is the gold standard for diagnostic and prognostic evaluation of PAH patients. However, this technique is highly invasive, so it is not used in routine clinical practice or patient follow-up. Thereby, it is essential to find new non-invasive strategies for evaluating disease progression. Biomarkers can be an effective solution for determining PAH patient prognosis and response to therapy, and aiding in diagnostic efforts, so long as their detection is non-invasive, easy, and objective. This review aims to clarify and describe some of the potential new candidates as circulating biomarkers of PAH.
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Affiliation(s)
- Joana Santos-Gomes
- UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Inês Gandra
- UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Rui Adão
- UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Frédéric Perros
- Paris-Porto Pulmonary Hypertension Collaborative Laboratory (3PH), UMR_S 999, INSERM, Université Paris-Saclay, Paris, France
- Université Paris–Saclay, AP-HP, INSERM UMR_S 999, Service de Pneumologie et Soins Intensifs Respiratoires, Hôpital de Bicêtre, Le Kremlin Bicêtre, France
| | - Carmen Brás-Silva
- UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
- Faculty of Nutrition and Food Sciences, University of Porto, Porto, Portugal
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11
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Jüttner AA, Danser AHJ, Roks AJM. Pharmacological developments in antihypertensive treatment through nitric oxide-cGMP modulation. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2022; 94:57-94. [PMID: 35659377 DOI: 10.1016/bs.apha.2022.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Treatment of hypertension until now has been directed at inhibition of vasoconstriction, of cardiac contractility and of blood volume regulation. Despite the arsenal of drugs available for this purpose, the control of target blood pressure is still a difficult goal to reach in outpatients. The nitric oxide-cyclic guanosine monophosphate signaling is one of the most important mediators of vasodilation. It might therefore be a potential and most welcome drug target for optimization of the treatment of hypertension. In this chapter we review the problems that can occur in this signaling system, the attempts that have been made to correct these problems, and those that are still under investigation. Recently developed, clinically safe medicines that are currently approved for other applications, such as myocardial infarction, await to be tested for essential systemic hypertension. We conclude that despite many years of research without translation, stimulation of nitric oxide-cyclic guanosine monophosphate is still a viable strategy in the prevention of the health risk posed by chronic hypertension.
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Affiliation(s)
- Annika A Jüttner
- Department of Internal Medicine, Division of Vascular Disease and Pharmacology, Erasmus Medical Center, Erasmus University, Rotterdam, The Netherlands
| | - A H Jan Danser
- Department of Internal Medicine, Division of Vascular Disease and Pharmacology, Erasmus Medical Center, Erasmus University, Rotterdam, The Netherlands
| | - Anton J M Roks
- Department of Internal Medicine, Division of Vascular Disease and Pharmacology, Erasmus Medical Center, Erasmus University, Rotterdam, The Netherlands.
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12
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Therapeutic augmentation of NO-sGC-cGMP signalling: lessons learned from pulmonary arterial hypertension and heart failure. Heart Fail Rev 2022; 27:1991-2003. [PMID: 35437713 DOI: 10.1007/s10741-022-10239-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/05/2022] [Indexed: 01/14/2023]
Abstract
The nitric oxide (NO)-guanylate cyclase (GC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in cardiovascular, pulmonary and renal function. Phosphodiesterase-5 inhibitors (PDE-5i) inhibit cGMP degradation, whereas both soluble guanylate cyclase (sGC) stimulators and sGC activators directly increase sGC. PDE-5i (e.g. sildenafil, tadalafil) and sGC stimulators (e.g. riociguat, vericiguat) have been extensively used in pulmonary artery hypertension (PAH) and heart failure (HF). PDE-5i have also been used in end-stage HF before and after left ventricular (LV) assist device (LVAD) implantation. Augmentation of NO-GC-cGMP signalling with PDE-5i causes selective pulmonary vasodilation, which is highly effective in PAH but may have controversial, potentially adverse effects in HF, including pre-LVAD implant due to device unmasking of PDE-5i-induced RV dysfunction. In contrast, retrospective analyses have demonstrated that PDE-5i have beneficial effects when initiated post LVAD implant due to the improved haemodynamics of the supported LV and the pleiotropic actions of these compounds. sGC stimulators, in turn, are effective both in PAH and in HF due to their balanced pulmonary and systemic vasodilation, and as such they are preferable to PDE-5i if the use of a pulmonary vasodilator is needed in HF patients, including those listed for LVAD implantation. Regarding the effectiveness of PDE-5i and sGC stimulators when initiated post LVAD implant, these two groups of compounds should be tested in a randomized control trial.
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13
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Inhibition of KIF23 Alleviates IPAH by Targeting Pyroptosis and Proliferation of PASMCs. Int J Mol Sci 2022; 23:ijms23084436. [PMID: 35457254 PMCID: PMC9032390 DOI: 10.3390/ijms23084436] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/10/2022] [Accepted: 04/11/2022] [Indexed: 12/04/2022] Open
Abstract
Idiopathic pulmonary arterial hypertension (IPAH) is a progressive vascular disease with high mortality and heritability. Pyroptosis is a novel form of programmed cell death, and it is closely associated with IPAH. However, the roles of pyroptosis-related genes (PRGs) in IPAH are still largely unknown. In this study, we identified KIF23 as the most relevant gene for IPAH and pyroptosis, and its expression was significantly increased in pulmonary arterial smooth muscle cells (PASMCs) of IPAH. Besides, the pyroptosis level of PASMCs was also considerably upregulated in IPAH. Knockdown of KIF23 in PASMCs could significantly suppress the PASMCs’ pyroptosis and proliferation and then alleviate the increase in pulmonary arterial pressure, right ventricular hypertrophy, and pulmonary vascular resistance in IPAH. KIF23 regulated the expression of Caspase3, NLRP3, and HMGB1, and they were all involved in the PI3K/AKT and MAPK pathways, indicating that PI3K/AKT and MAPK pathways might participate in regulating PASMCs pyroptosis by KIF23. In conclusion, our study suggests that KIF23 may be a new therapeutic target for IPAH, which can alleviate the symptoms of IPAH by inhibiting the pyroptosis and proliferation of PASMCs.
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14
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Sanati M, Aminyavari S, Mollazadeh H, Bibak B, Mohtashami E, Afshari AR. How do phosphodiesterase-5 inhibitors affect cancer? A focus on glioblastoma multiforme. Pharmacol Rep 2022; 74:323-339. [PMID: 35050491 DOI: 10.1007/s43440-021-00349-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 12/10/2021] [Accepted: 12/13/2021] [Indexed: 11/30/2022]
Abstract
Since the discovery of phosphodiesterase-5 (PDE5) enzyme overexpression in the central nervous system (CNS) malignancies, investigations have explored the potential capacity of current PDE5 inhibitor drugs for repositioning in the treatment of brain tumors, notably glioblastoma multiforme (GBM). It has now been recognized that these drugs increase brain tumors permeability and enhance standard chemotherapeutics effectiveness. More importantly, studies have highlighted the promising antitumor functions of PDE5 inhibitors, e.g., triggering apoptosis, suppressing tumor cell growth and invasion, and reversing tumor microenvironment (TME) immunosuppression in the brain. However, contradictory reports have suggested a pro-oncogenic role for neuronal cyclic guanosine monophosphate (cGMP), indicating the beneficial function of PDE5 in the brain of GBM patients. Unfortunately, due to the inconsistent preclinical findings, only a few clinical trials are evaluating the therapeutic value of PDE5 inhibitors in GBM treatment. Accordingly, additional studies should be conducted to shed light on the precise effect of PDE5 inhibitors in GBM biology regarding the existing molecular heterogeneities among individuals. Here, we highlighted and discussed the previously investigated mechanisms underlying the impacts of PDE5 inhibitors in cancers, focusing on GBM to provide an overview of current knowledge necessary for future studies.
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Affiliation(s)
- Mehdi Sanati
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran
| | - Samaneh Aminyavari
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Mollazadeh
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Bahram Bibak
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Elmira Mohtashami
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir R Afshari
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran.
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15
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Abstract
Inhaled nitric oxide (iNO) therapy had a transformational impact on the management of infants with persistent pulmonary hypertension of the newborn (PPHN). iNO remains the only approved pulmonary vasodilator for PPHN; yet 30% to 40% of patients do not respond or have incomplete response to iNO. Lung recruitment strategies with early surfactant administration and high-frequency ventilation can optimize the response to iNO in the presence of parenchymal lung diseases. Alternate pulmonary vasodilators are used commonly as rescue, life-saving measures, though there is a lack of high-quality evidence supporting their efficacy and safety. This article reviews the available evidence and future directions for research in PPHN.
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16
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Banjac NM, Vasović VM, Stilinović NP, Prodanović DV, Tomas Petrović AD, Vasović LV, Jakovljević VL. Tadalafil in Increasing Doses: The Influence on Coronary Blood Flow and Oxidative Stress in Isolated Rat Hearts. Pharmacology 2021; 107:150-159. [PMID: 34903698 DOI: 10.1159/000520498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 10/27/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION This study aimed to assess the influence of different doses of tadalafil on coronary flow and oxidative stress in isolated rat hearts. METHODS The hearts of male Wistar albino rats (n = 48) were retrogradely perfused according to the Langendorff technique at gradually increased constant perfusion pressure (CPP) (40-120 mm Hg). Coronary flow and oxidative stress markers: nitrite oxide (NO) outflow and superoxide anion production in coronary effluent were measured. The experiments were performed during control conditions and in the presence of tadalafil (10, 20, 50, and 200 nM) alone or with Nω-nitro-L-arginine monomethyl ester (L-NAME) (30 μM). RESULTS Tadalafil administration significantly increased coronary flow at all CPP values at all administered doses. Tadalafil led to an increase in the NO levels, but a statistically significant NO release increase was found only at the highest dose and highest CPP. Tadalafil did not significantly affect the release of O2-. After inhibiting the nitrite oxide synthase system by L-NAME, tadalafil-induced changes in cardiac flow and NO levels were reversed. L-NAME administration had no pronounced effect on the O2- release. CONCLUSION Tadalafil causes changes in the heart vasculature in a dose-dependent manner. It does not lead to a significant increase in the production of superoxide anion radicals.
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Affiliation(s)
- Nada M Banjac
- University of Banja Luka, Faculty of Medicine, Banja Luka, Bosnia and Herzegovina
| | - Velibor M Vasović
- Department of Pharmacology, Toxicology and Clinical Pharmacology, University of Novi Sad, Faculty of Medicine, Novi Sad, Serbia
| | - Nebojša P Stilinović
- Department of Pharmacology, Toxicology and Clinical Pharmacology, University of Novi Sad, Faculty of Medicine, Novi Sad, Serbia
| | - Dušan V Prodanović
- Department of Pharmacology, Toxicology and Clinical Pharmacology, University of Novi Sad, Faculty of Medicine, Novi Sad, Serbia
| | - Ana D Tomas Petrović
- Department of Pharmacology, Toxicology and Clinical Pharmacology, University of Novi Sad, Faculty of Medicine, Novi Sad, Serbia
| | | | - Vladimir Lj Jakovljević
- Department of Physiology, University of Kragujevac, Faculty of Medical Sciences, Kragujevac, Serbia
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17
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Bailey JJ, Wuest M, Bojovic T, Kronemann T, Wängler C, Wängler B, Wuest F, Schirrmacher R. On the Viability of Tadalafil-Based 18F-Radiotracers for In Vivo Phosphodiesterase 5 (PDE5) PET Imaging. ACS OMEGA 2021; 6:21741-21754. [PMID: 34471776 PMCID: PMC8388084 DOI: 10.1021/acsomega.1c03315] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 07/29/2021] [Indexed: 06/13/2023]
Abstract
Phosphodiesterase 5 (PDE5) is a clinically relevant biomarker and therapeutic target for many human pathologies, yet a noninvasive agent for the assessment of PDE5 expression has yet to be realized. Such agents would improve our understanding of the nitric oxide (NO)/cyclic guanosine 3',5'-monophosphate (cGMP)/PDE5 pathway in human pathologies and potentially lead to novel uses of PDE5 inhibitors to manage lung conditions like SARS-CoV-2-mediated pulmonary inflammatory responses. In this study, efforts were made to produce an 18F-labeled analogue of the PDE5 inhibitor tadalafil to visualize PDE5 expression in vivo with positron emission tomography (PET). However, during the late-stage fluorination step, quantitative epimerization of the tadalafil C12a stereocenter occurred, yielding a less active epi-isomer. In vivo dynamic microPET images in mice revealed that the epimerized radiotracer, [18F]epi-18, rapidly accumulated in the liver with negligible uptake in tissues of known PDE5 expression.
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Affiliation(s)
- Justin J. Bailey
- Department
of Oncology, Cross Cancer Institute, University
of Alberta, Edmonton, Alberta T6G 1Z2, Canada
| | - Melinda Wuest
- Department
of Oncology, Cross Cancer Institute, University
of Alberta, Edmonton, Alberta T6G 1Z2, Canada
| | - Tamara Bojovic
- Department
of Oncology, Cross Cancer Institute, University
of Alberta, Edmonton, Alberta T6G 1Z2, Canada
| | - Travis Kronemann
- Department
of Oncology, Cross Cancer Institute, University
of Alberta, Edmonton, Alberta T6G 1Z2, Canada
| | - Carmen Wängler
- Biomedical Chemistry, Department
of Clinical Radiology and Nuclear
Medicine and Molecular Imaging and Radiochemistry, Department of Clinical Radiology
and Nuclear Medicine, Medical Faculty Mannheim
of Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim 68167, Germany
| | - Björn Wängler
- Biomedical Chemistry, Department
of Clinical Radiology and Nuclear
Medicine and Molecular Imaging and Radiochemistry, Department of Clinical Radiology
and Nuclear Medicine, Medical Faculty Mannheim
of Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim 68167, Germany
| | - Frank Wuest
- Department
of Oncology, Cross Cancer Institute, University
of Alberta, Edmonton, Alberta T6G 1Z2, Canada
| | - Ralf Schirrmacher
- Department
of Oncology, Cross Cancer Institute, University
of Alberta, Edmonton, Alberta T6G 1Z2, Canada
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18
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Bayarri MA, Milara J, Estornut C, Cortijo J. Nitric Oxide System and Bronchial Epithelium: More Than a Barrier. Front Physiol 2021; 12:687381. [PMID: 34276407 PMCID: PMC8279772 DOI: 10.3389/fphys.2021.687381] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 06/07/2021] [Indexed: 12/24/2022] Open
Abstract
Airway epithelium forms a physical barrier that protects the lung from the entrance of inhaled allergens, irritants, or microorganisms. This epithelial structure is maintained by tight junctions, adherens junctions and desmosomes that prevent the diffusion of soluble mediators or proteins between apical and basolateral cell surfaces. This apical junctional complex also participates in several signaling pathways involved in gene expression, cell proliferation and cell differentiation. In addition, the airway epithelium can produce chemokines and cytokines that trigger the activation of the immune response. Disruption of this complex by some inflammatory, profibrotic, and carcinogens agents can provoke epithelial barrier dysfunction that not only contributes to an increase of viral and bacterial infection, but also alters the normal function of epithelial cells provoking several lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) or lung cancer, among others. While nitric oxide (NO) molecular pathway has been linked with endothelial function, less is known about the role of the NO system on the bronchial epithelium and airway epithelial cells function in physiological and different pathologic scenarios. Several data indicate that the fraction of exhaled nitric oxide (FENO) is altered in lung diseases such as asthma, COPD, lung fibrosis, and cancer among others, and that reactive oxygen species mediate uncoupling NO to promote the increase of peroxynitrite levels, thus inducing bronchial epithelial barrier dysfunction. Furthermore, iNOS and the intracellular pathway sGC-cGMP-PKG are dysregulated in bronchial epithelial cells from patients with lung inflammation, fibrosis, and malignancies which represents an attractive drug molecular target. In this review we describe in detail current knowledge of the effect of NOS-NO-GC-cGMP-PKG pathway activation and disruption in bronchial epithelial cells barrier integrity and its contribution in different lung diseases, focusing on bronchial epithelial cell permeability, inflammation, transformation, migration, apoptosis/necrosis, and proliferation, as well as the specific NO molecular pathways involved.
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Affiliation(s)
- María Amparo Bayarri
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Javier Milara
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain
- Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), Health Institute Carlos III, Madrid, Spain
- Pharmacy Unit, University General Hospital Consortium of Valencia, Valencia, Spain
| | - Cristina Estornut
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Julio Cortijo
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain
- Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), Health Institute Carlos III, Madrid, Spain
- Research and Teaching Unit, University General Hospital Consortium of Valencia, Valencia, Spain
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19
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Ouranidis A, Tsiaxerli A, Vardaka E, Markopoulou CK, Zacharis CK, Nicolaou I, Hatzichristou D, Haidich AB, Kostomitsopoulos N, Kachrimanis K. Sildenafil 4.0-Integrated Synthetic Chemistry, Formulation and Analytical Strategies Effecting Immense Therapeutic and Societal Impact in the Fourth Industrial Era. Pharmaceuticals (Basel) 2021; 14:365. [PMID: 33920975 PMCID: PMC8071249 DOI: 10.3390/ph14040365] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 04/08/2021] [Accepted: 04/09/2021] [Indexed: 12/14/2022] Open
Abstract
Sildenafil is a potent selective, reversible inhibitor of phosphodiesterase type 5 (PDE5) approved for the treatment of erectile dysfunction and pulmonary arterial hypertension. Whilst twenty years have passed since its original approval by the US Food and Drug Administration (USFDA), sildenafil enters the fourth industrial era catalyzing the treatment advances against erectile dysfunction and pulmonary hypertension. The plethora of detailed clinical data accumulated and the two sildenafil analogues marketed, namely tadalafil and vardenafil, signify the relevant therapeutic and commercial achievements. The pharmacokinetic and pharmacodynamic behavior of the drug appears complex, interdependent and of critical importance whereas the treatment of special population cohorts is considered. The diversity of the available formulation strategies and their compatible administration routes, extend from tablets to bolus suspensions and from per os to intravenous, respectively, inheriting the associated strengths and weaknesses. In this comprehensive review, we attempt to elucidate the multi-disciplinary elements spanning the knowledge fields of chemical synthesis, physicochemical properties, pharmacology, clinical applications, biopharmaceutical profile, formulation approaches for different routes of administration and analytical strategies, currently employed to guide the development of sildenafil-based compositions.
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Affiliation(s)
- Andreas Ouranidis
- Department of Pharmaceutical Technology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (A.T.); (E.V.)
- Department of Chemical Engineering, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Anastasia Tsiaxerli
- Department of Pharmaceutical Technology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (A.T.); (E.V.)
| | - Elisavet Vardaka
- Department of Pharmaceutical Technology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (A.T.); (E.V.)
| | - Catherine K. Markopoulou
- Laboratory of Pharmaceutical Analysis, Department of Pharmaceutical Technology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (C.K.M.); (C.K.Z.)
| | - Constantinos K. Zacharis
- Laboratory of Pharmaceutical Analysis, Department of Pharmaceutical Technology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (C.K.M.); (C.K.Z.)
| | - Ioannis Nicolaou
- Laboratory of Pharmaceutical Chemistry, Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Dimitris Hatzichristou
- Department of Urology, Medical School, Aristotle University of Thessaloniki, 54635 Thessaloniki, Greece;
| | - Anna-Bettina Haidich
- Department of Hygiene, Social-Preventive Medicine and Medical Statistics, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Nikolaos Kostomitsopoulos
- Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece;
| | - Kyriakos Kachrimanis
- Department of Pharmaceutical Technology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (A.T.); (E.V.)
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20
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Lázár Z, Mészáros M, Bikov A. The Nitric Oxide Pathway in Pulmonary Arterial Hypertension: Pathomechanism, Biomarkers and Drug Targets. Curr Med Chem 2021; 27:7168-7188. [PMID: 32442078 DOI: 10.2174/0929867327666200522215047] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 01/03/2020] [Accepted: 02/20/2020] [Indexed: 11/22/2022]
Abstract
The altered Nitric Oxide (NO) pathway in the pulmonary endothelium leads to increased vascular smooth muscle tone and vascular remodelling, and thus contributes to the development and progression of pulmonary arterial hypertension (PAH). The pulmonary NO signalling is abrogated by the decreased expression and dysfunction of the endothelial NO synthase (eNOS) and the accumulation of factors blocking eNOS functionality. The NO deficiency of the pulmonary vasculature can be assessed by detecting nitric oxide in the exhaled breath or measuring the degradation products of NO (nitrite, nitrate, S-nitrosothiol) in blood or urine. These non-invasive biomarkers might show the potential to correlate with changes in pulmonary haemodynamics and predict response to therapies. Current pharmacological therapies aim to stimulate pulmonary NO signalling by suppressing the degradation of NO (phosphodiesterase- 5 inhibitors) or increasing the formation of the endothelial cyclic guanosine monophosphate, which mediates the downstream effects of the pathway (soluble guanylate cyclase sensitizers). Recent data support that nitrite compounds and dietary supplements rich in nitrate might increase pulmonary NO availability and lessen vascular resistance. This review summarizes current knowledge on the involvement of the NO pathway in the pathomechanism of PAH, explores novel and easy-to-detect biomarkers of the pulmonary NO.
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Affiliation(s)
- Zsófia Lázár
- Department of Pulmonology, Semmelweis University, Budapest, Hungary
| | - Martina Mészáros
- Department of Pulmonology, Semmelweis University, Budapest, Hungary
| | - Andras Bikov
- Department of Pulmonology, Semmelweis University, Budapest, Hungary,Manchester University NHS Foundation Trust, Manchester, United Kingdom
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21
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Ghosh A, Koziol-White CJ, Jester WF, Erzurum SC, Asosingh K, Panettieri RA, Stuehr DJ. An inherent dysfunction in soluble guanylyl cyclase is present in the airway of severe asthmatics and is associated with aberrant redox enzyme expression and compromised NO-cGMP signaling. Redox Biol 2021; 39:101832. [PMID: 33360351 PMCID: PMC7772568 DOI: 10.1016/j.redox.2020.101832] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/05/2020] [Accepted: 12/08/2020] [Indexed: 12/19/2022] Open
Abstract
A subset of asthmatics develop a severe form of the disease whose etiology involves airway inflammation along with inherent drivers that remain ill-defined. To address this, we studied human airway smooth muscle cells (HASMC), whose relaxation drives airway bronchodilation and whose dysfunction contributes to airway obstruction and hypersensitivity in severe asthma. Because HASMC relaxation can be driven by the NO-soluble guanylyl cyclase (sGC)-cGMP signaling pathway, we questioned if HASMC from severe asthma donors might possess inherent defects in their sGC or in redox enzymes that support sGC function. We analyzed HASMC primary lines derived from 17 severe asthma and 16 normal donors and corresponding lung tissue samples regarding sGC activation by NO or by pharmacologic agonists, and also determined expression levels of sGC α1 and β1 subunits, supporting redox enzymes, and related proteins. We found a majority of the severe asthma donor HASMC (12/17) and lung samples primarily expressed a dysfunctional sGC that was NO-unresponsive and had low heterodimer content and high Hsp90 association. This sGC phenotype correlated with lower expression levels of the supporting redox enzymes cytochrome b5 reductase, catalase, and thioredoxin-1, and higher expression of heme oxygenases 1 and 2. Together, our work reveals that severe asthmatics are predisposed toward defective NO-sGC-cGMP signaling in their airway smooth muscle due to an inherent sGC dysfunction, which in turn is associated with inherent changes in the cell redox enzymes that impact sGC maturation and function.
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Affiliation(s)
- Arnab Ghosh
- Department of Inflammation and Immunity, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH, 44195, USA.
| | - Cynthia J Koziol-White
- Rutgers Institute for Translational Medicine and Science, Rutgers University, New Brunswick, NJ, 08901, USA
| | - William F Jester
- Rutgers Institute for Translational Medicine and Science, Rutgers University, New Brunswick, NJ, 08901, USA
| | - Serpil C Erzurum
- Department of Inflammation and Immunity, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Kewal Asosingh
- Department of Inflammation and Immunity, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Reynold A Panettieri
- Rutgers Institute for Translational Medicine and Science, Rutgers University, New Brunswick, NJ, 08901, USA
| | - Dennis J Stuehr
- Department of Inflammation and Immunity, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH, 44195, USA.
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22
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Chen S, Yan C. An update of cyclic nucleotide phosphodiesterase as a target for cardiac diseases. Expert Opin Drug Discov 2021; 16:183-196. [PMID: 32957823 PMCID: PMC7854486 DOI: 10.1080/17460441.2020.1821643] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 09/07/2020] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Cyclic nucleotides, cAMP, and cGMP, are important second messengers of intracellular signaling and play crucial roles in cardiovascular biology and diseases. Cyclic nucleotide phosphodiesterases (PDEs) control the duration, magnitude, and compartmentalization of cyclic nucleotide signaling by catalyzing the hydrolysis of cyclic nucleotides. Individual PDEs modulate distinct signaling pathways and biological functions in the cell, making it a potential therapeutic target for the treatment of different cardiovascular disorders. The clinical success of several PDE inhibitors has ignited continued interest in PDE inhibitors and in PDE-target therapeutic strategies. AREAS COVERED This review concentrates on recent research advances of different PDE isoforms with regard to their expression patterns and biological functions in the heart. The limitations of current research and future directions are then discussed. The current and future development of PDE inhibitors is also covered. EXPERT OPINION Despite the therapeutic success of several marketed PDE inhibitors, the use of PDE inhibitors can be limited by their side effects, lack of efficacy, and lack of isoform selectivity. Advances in our understanding of the mechanisms by which cellular functions are changed through PDEs may enable the development of new approaches to achieve effective and specific PDE inhibition for various cardiac therapies.
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Affiliation(s)
- Si Chen
- Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
- Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Chen Yan
- Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
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23
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Stadlbauer C, Golovchenko S, Englert L, Spaeth M, Hoenicka M, Hofmann HS, Ried M. [Organ Bath Experiments on Human Pulmonary Vessels: Assessment of Drug Efficacy for Treatment of Pulmonary Arterial Hypertension]. Pneumologie 2021; 75:369-376. [PMID: 33472251 DOI: 10.1055/a-1332-6892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Various vasodilator medications are used in the treatment of pulmonary arterial hypertension (PAH), such as endothelin receptor antagonists (ERA) or phosphodiesterase-5-(PDE-5-)inhibitors. In a human ex vivo model, we investigated whether the combination of two substance classes could achieve a higher effect or - without loss of vasodilatation - a lower dosage of the individual substances might be sufficient. We established an ex vivo organ bath model to evaluate the dose-dependent effects of ERA and PDE-5-inhibitors on pulmonary vessels harvested from patients who underwent surgery (lung resection/transplantation). We compared the combined use of both substance classes with administration of one class of drugs alone. Due to the limitations of the experimental design, it is not possible to extrapolate our results to the conditions in vivo. Nevertheless, organ bath proved to be helpful in evaluating the dose-dependent effects of ERA and PDE-5 inhibitors, which is not practical in everyday clinical practice. In this setting, the effectiveness of the combination therapy and the potential for dose reduction depended on the concentrations used and on the influence of previous illnesses on blood vessel function. This article describes the most important results of our experimental investigations and suggestions for future projects.
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Affiliation(s)
- C Stadlbauer
- Klinik und Poliklinik für Herz-, Thorax- und herznahe Gefäßchirurgie, Universitätsklinikum Regensburg, Regensburg
| | - S Golovchenko
- Klinik und Poliklinik für Herz-, Thorax- und herznahe Gefäßchirurgie, Universitätsklinikum Regensburg, Regensburg
| | - L Englert
- Klinik und Poliklinik für Herz-, Thorax- und herznahe Gefäßchirurgie, Universitätsklinikum Regensburg, Regensburg
| | - M Spaeth
- Klinik und Poliklinik für Herz-, Thorax- und herznahe Gefäßchirurgie, Universitätsklinikum Regensburg, Regensburg
| | - M Hoenicka
- Klinik für Herz- und Thoraxchirurgie, Universitätsklinikum Ulm, Ulm
| | - H-S Hofmann
- Klinik und Poliklinik für Herz-, Thorax- und herznahe Gefäßchirurgie, Universitätsklinikum Regensburg, Regensburg.,Klinik für Thoraxchirurgie, Krankenhaus Barmherzige Brüder Regensburg, Regensburg
| | - M Ried
- Klinik und Poliklinik für Herz-, Thorax- und herznahe Gefäßchirurgie, Universitätsklinikum Regensburg, Regensburg
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Abstract
Cyclic guanosine 3',5'-monophosphate (cGMP) is the key second messenger molecule in nitric oxide signaling. Its rapid generation and fate, but also its role in mediating acute cellular functions has been extensively studied. In the past years, genetic studies suggested an important role for cGMP in affecting the risk of chronic cardiovascular diseases, for example, coronary artery disease and myocardial infarction. Here, we review the role of cGMP in atherosclerosis and other cardiovascular diseases and discuss recent genetic findings and identified mechanisms. Finally, we highlight open questions and promising research topics.
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Mostafa T. Could Oral Phosphodiesterase 5 Inhibitors Have a Potential Adjuvant Role in Combating COVID-19 Infection? Sex Med Rev 2021; 9:15-22. [PMID: 33077403 PMCID: PMC7833179 DOI: 10.1016/j.sxmr.2020.08.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 08/16/2020] [Accepted: 08/17/2020] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The recent global outbreak of coronavirus disease 2019 (COVID-19) has become a pandemic with a lot of sufferers. Excessive inflammation, exaggerated immune response, with ultimate apoptosis contribute to COVID-19 pathology that progress to acute lung acute respiratory distress. OBJECTIVE To shed a light on the likely benefits of the oral phosphodiesterase 5 (PDE5) inhibitor adjuvant role in combating COVID-19 infection. METHODS A literature review was performed in the PubMed/Medline database, Scopus, Cochrane Library, EMBASE, Academic Search Complete, Google Scholar, and CINAHL databases using the keywords COVID-19; phosphodiesterase-5 inhibitors; cytokine storm; respiratory distress. RESULTS Despite the worsening trends of COVID-19, still no drugs are validated to have significant clinical efficacy in the treatment of patients with COVID-19 in large-scale studies. While the progress toward a curative agent and/or vaccine is certainly hopeful, the principal limiting factor in such public health emergencies is always the time. Therefore, a preexisting licensed therapeutic(s) might offer a reprieve to the healthcare systems operating at the edge of capacity. In this context, the innovation of oral PDE5 inhibitors with their valuable effects on erection have provided a breakthrough in the treatment of erectile dysfunction and opened new fields of clinical application for this class of drugs. Oral PDE5 inhibitors have been demonstrated to possess many beneficial useful additional implications with acknowledged anti-inflammatory, antioxidant, immune response regulation, and antiapoptotic properties. These properties have been elucidated through the nitric oxide/soluble guanylyl cyclase/cyclic guanylate monophosphate pathway in addition to the emerged hemeoxygenase-1 enzyme as well as hydrogen sulfide pathways. These properties could support repurposing oral PDE5 inhibitors' potential adjuvant use in targeting different aspects of COVID-19 infection. CONCLUSION Oral PDE5 inhibitors retain several acknowledged off-labeled useful implications with anti-inflammatory, antioxidant, immune response regulation, and antiapoptotic properties. These properties may support repurposing oral PDE5 inhibitors' potential adjuvant use in the protocols combating COVID-19 manifestations. Mostafa T. Could Oral Phosphodiesterase 5 Inhibitors Have a Potential Adjuvant Role in Combating Coronavirus Disease 2019 Infection? Sex Med Rev 2021;9:15-22.
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Affiliation(s)
- Taymour Mostafa
- Andrology, Sexology & STIs Department, Faculty of Medicine, Cairo University, Cairo, Egypt.
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26
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Friebe A, Englert N. NO-sensitive guanylyl cyclase in the lung. Br J Pharmacol 2020; 179:2328-2343. [PMID: 33332689 DOI: 10.1111/bph.15345] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 12/09/2020] [Accepted: 12/10/2020] [Indexed: 12/21/2022] Open
Abstract
In the late 1960s, several labatories identified guanylyl cyclase (GC) as the cGMP-producing enzyme. Subsequently, two different types of GC were described that differed in their cellular localization. Primarily found in the cytosol, nitric oxide (NO)-sensitive guanylyl cyclase (NO-GC) acts as receptor for the signalling molecule NO, in contrast the membrane-bound isoenzyme is activated by natriuretic peptides. The lung compared with other tissues exhibits the highest expression of NO-GC. The enzyme has been purified from lung for biochemical analysis. Although expressed in smooth muscle cells (SMCs) and in pericytes, the function of NO-GC in lung, especially in pericytes, is still not fully elucidated. However, pharmacological compounds that target NO-GC are available and have been implemented for the therapy of pulmonary arterial hypertension. In addition, NO-GC has been suggested as drug target for the therapy of asthma, acute respiratory distress syndrome and pulmonary fibrosis.
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Affiliation(s)
- Andreas Friebe
- Physiological Institute, Julius Maximilian University of Würzburg, Würzburg, Germany
| | - Nils Englert
- Physiological Institute, Julius Maximilian University of Würzburg, Würzburg, Germany
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27
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Could Oral Phosphodiesterase 5 Inhibitors Have a Potential Adjuvant Role in Combating COVID-19 Infection? Sex Med Rev 2020. [PMID: 33077403 DOI: 10.1016/j.sxmr.2020.08.006.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
INTRODUCTION The recent global outbreak of coronavirus disease 2019 (COVID-19) has become a pandemic with a lot of sufferers. Excessive inflammation, exaggerated immune response, with ultimate apoptosis contribute to COVID-19 pathology that progress to acute lung acute respiratory distress. OBJECTIVE To shed a light on the likely benefits of the oral phosphodiesterase 5 (PDE5) inhibitor adjuvant role in combating COVID-19 infection. METHODS A literature review was performed in the PubMed/Medline database, Scopus, Cochrane Library, EMBASE, Academic Search Complete, Google Scholar, and CINAHL databases using the keywords COVID-19; phosphodiesterase-5 inhibitors; cytokine storm; respiratory distress. RESULTS Despite the worsening trends of COVID-19, still no drugs are validated to have significant clinical efficacy in the treatment of patients with COVID-19 in large-scale studies. While the progress toward a curative agent and/or vaccine is certainly hopeful, the principal limiting factor in such public health emergencies is always the time. Therefore, a preexisting licensed therapeutic(s) might offer a reprieve to the healthcare systems operating at the edge of capacity. In this context, the innovation of oral PDE5 inhibitors with their valuable effects on erection have provided a breakthrough in the treatment of erectile dysfunction and opened new fields of clinical application for this class of drugs. Oral PDE5 inhibitors have been demonstrated to possess many beneficial useful additional implications with acknowledged anti-inflammatory, antioxidant, immune response regulation, and antiapoptotic properties. These properties have been elucidated through the nitric oxide/soluble guanylyl cyclase/cyclic guanylate monophosphate pathway in addition to the emerged hemeoxygenase-1 enzyme as well as hydrogen sulfide pathways. These properties could support repurposing oral PDE5 inhibitors' potential adjuvant use in targeting different aspects of COVID-19 infection. CONCLUSION Oral PDE5 inhibitors retain several acknowledged off-labeled useful implications with anti-inflammatory, antioxidant, immune response regulation, and antiapoptotic properties. These properties may support repurposing oral PDE5 inhibitors' potential adjuvant use in the protocols combating COVID-19 manifestations. Mostafa T. Could Oral Phosphodiesterase 5 Inhibitors Have a Potential Adjuvant Role in Combating Coronavirus Disease 2019 Infection? Sex Med Rev 2021;9:15-22.
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MiR-200a inversely correlates with Hedgehog and TGF-β canonical/non-canonical trajectories to orchestrate the anti-fibrotic effect of Tadalafil in a bleomycin-induced pulmonary fibrosis model. Inflammopharmacology 2020; 29:167-182. [PMID: 32914382 DOI: 10.1007/s10787-020-00748-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 08/25/2020] [Indexed: 12/17/2022]
Abstract
Few reports have documented the ability of phosphodiesterase-5 inhibitors (PDE-5-Is) to ameliorate idiopathic pulmonary fibrosis (IPF) mainly by their anti-inflammatory/antioxidant capacities, without unveiling the possible molecular mechanisms involved. Because of the recent role of miR-200 family and Sonic Hedgehog (SHH) trajectory in IPF, we have studied their impact on the anti-fibrotic potential of tadalafil against bleomycin-induced pulmonary fibrosis. Animals were allocated into normal-control, bleomycin-fibrotic control, and bleomycin post-treated with tadalafil or dexamethasone, as the reference drug. On the molecular level, tadalafil has reverted the bleomycin effect on all the assessed parameters. Tadalafil upregulated the gene expression of miR-200a, but decreased the smoothened (SMO) and the transcription factors glioma-associated oncogene homolog (Gli-1, Gli-2), members of SHH pathway. Additionally, tadalafil ebbed transforming growth factor (TGF)-β, its canonical (SMAD-3/alpha smooth muscle actin [α-SMA] and Snail), and non-canonical (p-Akt/p-Forkhead box O3 (FOXO3) a) pathways. Besides, a strong negative correlation between miR-200a and the analyzed pathways was proved. The effect of tadalafil was further confirmed by the improved lung structure and the reduced Ashcroft score/collagen deposition. The results were comparable to that of dexamethasone. In conclusion, our study has highlighted the involvement of miR-200a in the anti-fibrotic effect of tadalafil with the inhibition of SHH hub and the pro-fibrotic pathways (TGF-β/ SMAD-3/α-SMA, Snail and p-AKT/p-FOXO3a). Potential anti-fibrotic effect of tadalafil. Modulation of miR200a/SHH/canonical and non-canonical TGF-β trajectories. → : stimulatory effect; ┴: inhibitory effect.
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Ammar HO, Tadros MI, Salama NM, Ghoneim AM. Ethosome-Derived Invasomes as a Potential Transdermal Delivery System for Vardenafil Hydrochloride: Development, Optimization and Application of Physiologically Based Pharmacokinetic Modeling in Adults and Geriatrics. Int J Nanomedicine 2020; 15:5671-5685. [PMID: 32821096 PMCID: PMC7418156 DOI: 10.2147/ijn.s261764] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 07/08/2020] [Indexed: 01/15/2023] Open
Abstract
Aim The aim of the current work was to develop vardenafil hydrochloride (VRD)-loaded ethosome-derived invasomes as a possible transdermal system which could be used for patients suffering from pulmonary arterial hypertension. Methods VRD-loaded ethosomes were developed at three concentrations of phosphatidylcholine (5, 10 and 15 mg/mL) and three percentages of ethanol (20%, 30% and 40%, v/v). The best achieved VRD-loaded ethosomes (ETH9) were optimized to invasomes via incorporation of terpenes (limonene, cineole and a 1:1 mixture) at three concentrations (0.5%, 1% and 2%, v/v). All systems were evaluated for vesicle size, zeta potential, drug entrapment efficiency (EE%), cumulative drug permeated percentages after 0.5hrs (Q0.5h) and 12hrs (Q12h) and steady-state flux (Jss). The optimized system (ETH9-INV8) was further characterized for morphology, histopathology and confocal laser scanning microscopy (CLSM). Physiologically based pharmacokinetic (PBPK) modeling was employed to estimate VRD pharmacokinetic parameters from the optimized transdermal system and an oral aqueous drug dispersion, in adults and geriatrics. Results The optimized invasomal system (ETH9-INV8) was characterized with spherical vesicles (159.9 nm) possessing negative zeta potential (-20.3 mV), promising EE% (81.3%), low Q0.5h (25.4%), high Q12h (85.3%) and the largest steady-state flux (6.4 µg.cm-2h-1). Following a leave-on period of 12hrs in rats, it showed minor histopathologic changes. CLSM studies proved its ability to deeply permeate rat skin. Lower Cmax values, delayed Tmax estimates and greater AUC0-24h folds in adults and geriatrics (≈ 2.18 and 1.69, respectively) were estimated following the transdermal application of ETH9-INV8 system. Conclusion ETH9-INV8 is a promising transdermal system for VRD.
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Affiliation(s)
- Hussein O Ammar
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt (FUE), New Cairo, Egypt
| | - Mina Ibrahim Tadros
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Nahla M Salama
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt (FUE), New Cairo, Egypt
| | - Amira Mohsen Ghoneim
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt (FUE), New Cairo, Egypt
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30
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Isidori AM, Giannetta E, Pofi R, Venneri MA, Gianfrilli D, Campolo F, Mastroianni CM, Lenzi A, d'Ettorre G. Targeting the NO-cGMP-PDE5 pathway in COVID-19 infection. The DEDALO project. Andrology 2020; 9:33-38. [PMID: 32526061 PMCID: PMC7307129 DOI: 10.1111/andr.12837] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 06/04/2020] [Accepted: 06/05/2020] [Indexed: 01/08/2023]
Abstract
Background A pandemic outbreak of COVID‐19 has been sweeping the world since December. It begins as a respiratory infection that, mainly in men with diabetes or renal impairment, evolves into a systemic disease, with SARDS, progressive endothelial cell damage, abnormal clotting and impaired cardiovascular and liver function. Some clinical trials are testing biological drugs to limit the immune system dysregulation, “cytokines storm,” that causes the systemic complications of COVID‐19. The contraindications of these drugs and their cost raise concerns over the implications of their widespread availability. Objectives Numerous clinical and experimental studies have revealed a role for the nitric oxide (NO)‐cyclic GMP‐phosphodiesterase type 5 (PDE5) pathway in modulating low‐grade inflammation in patients with metabolic diseases, offering cardiovascular protection. PDE5 inhibition favors an anti‐inflammatory response by modulating activated T cells, reducing cytokine release, lowering fibrosis, increasing oxygen diffusion, stimulating vascular repair. PDE5 is highly expressed in the lungs, where its inhibition improves pulmonary fibrosis, a complication of severe COVID‐19 disease. Materials and methods We performed a systematic review of all evidence documenting any involvement of the NO‐cGMP‐PDE5 axis in the pathophysiology of COVID‐19, presenting the ongoing clinical trials aimed at modulating this axis, including our own “silDEnafil administration in DiAbetic and dysmetaboLic patients with COVID‐19 (DEDALO trial).” Results The reviewed evidence suggests that PDE5 inhibitors could offer a new strategy in managing COVID‐19 by (i) counteracting the Ang‐II‐mediated downregulation of AT‐1 receptor; (ii) acting on monocyte switching, thus reducing pro‐inflammatory cytokines, interstitial infiltration and the vessel damage responsible for alveolar hemorrhage‐necrosis; (iii) inhibiting the transition of endothelial and smooth muscle cells to mesenchymal cells in the pulmonary artery, preventing clotting and thrombotic complications. Discussion and Conclusion If the ongoing trials presented herein should provide positive findings, the low cost, wide availability and temperature stability of PDE5 inhibitors could make them a major resource to combat COVID‐19 in developing countries.
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Affiliation(s)
- Andrea M Isidori
- Department of Experimental Medicine, Sapienza" University of Rome, Rome, Italy
| | - Elisa Giannetta
- Department of Experimental Medicine, Sapienza" University of Rome, Rome, Italy
| | - Riccardo Pofi
- Department of Experimental Medicine, Sapienza" University of Rome, Rome, Italy
| | - Mary A Venneri
- Department of Experimental Medicine, Sapienza" University of Rome, Rome, Italy
| | - Daniele Gianfrilli
- Department of Experimental Medicine, Sapienza" University of Rome, Rome, Italy
| | - Federica Campolo
- Department of Experimental Medicine, Sapienza" University of Rome, Rome, Italy
| | - Claudio M Mastroianni
- Department of Public Health and Infectious Diseases, "Sapienza" University of Rome, Policlinico Umberto I of Rome, Rome, Italy
| | - Andrea Lenzi
- Department of Experimental Medicine, Sapienza" University of Rome, Rome, Italy
| | - Gabriella d'Ettorre
- Department of Public Health and Infectious Diseases, "Sapienza" University of Rome, Policlinico Umberto I of Rome, Rome, Italy
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Cesarini V, Guida E, Campolo F, Crescioli C, Di Baldassarre A, Pisano C, Balistreri CR, Ruvolo G, Jannini EA, Dolci S. Type 5 phosphodiesterase (PDE5) and the vascular tree: From embryogenesis to aging and disease. Mech Ageing Dev 2020; 190:111311. [PMID: 32628940 PMCID: PMC7333613 DOI: 10.1016/j.mad.2020.111311] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 06/20/2020] [Accepted: 07/02/2020] [Indexed: 12/13/2022]
Abstract
Vascular development depends on the timely differentiation of endothelial and smooth muscle cells. Vascular aging and vascular disease are influenced by endothelial and vascular smooth muscle cell compartments. A survey of the literature on the role of PDE5 in vascular development, aging and disease is reported. The role of PDE5 on vascular development, aging and disease needs to be further investigated by its genetic ablation. Vascular tree development depends on the timely differentiation of endothelial and vascular smooth muscle cells. These latter are key players in the formation of the vascular scaffold that offers resistance to the blood flow. This review aims at providing an overview on the role of PDE5, the cGMP-specific phosphodiesterase that historically attracted much attention for its involvement in male impotence, in the regulation of vascular smooth muscle cell function. The overall goal is to underscore the importance of PDE5 expression and activity in this cell type in the context of the organs where its function has been extensively studied.
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Affiliation(s)
| | - Eugenia Guida
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Federica Campolo
- Department of Experimental Medicine, University of Rome La Sapienza, Rome, Italy
| | - Clara Crescioli
- Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | | | - Calogera Pisano
- Department of Surgical Sciences, University of Rome Tor Vergata, Rome, Italy
| | - Carmela Rita Balistreri
- Department of Bio-Medicine, Neuroscience, and Advanced Diagnostics (Bi.N.D.), University of Palermo, Palermo, Italy
| | - Giovanni Ruvolo
- Department of Surgical Sciences, University of Rome Tor Vergata, Rome, Italy
| | | | - Susanna Dolci
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
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Ribaudo G, Ongaro A, Zagotto G, Memo M, Gianoncelli A. Therapeutic Potential of Phosphodiesterase Inhibitors against Neurodegeneration: The Perspective of the Medicinal Chemist. ACS Chem Neurosci 2020; 11:1726-1739. [PMID: 32401481 PMCID: PMC8007108 DOI: 10.1021/acschemneuro.0c00244] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
![]()
Increasing human
life expectancy prompts the development of novel
remedies for cognitive decline: 44 million people worldwide are affected
by dementia, and this number is predicted to triple by 2050. Acetylcholinesterase
and N-methyl-d-aspartate receptors represent
the targets of currently available drugs for Alzheimer’s disease,
which are characterized by limited efficacy. Thus, the search for
therapeutic agents with alternative or combined mechanisms of action
is wide open. Since variations in 3′,5′-cyclic adenosine
monophosphate, 3′,5′-cyclic guanosine monophosphate,
and/or nitric oxide levels interfere with downstream pathways involved
in memory processes, evidence supporting the potential of phosphodiesterase
(PDE) inhibitors in contrasting neurodegeneration should be
critically considered. For the preparation of this Review, more than
140 scientific papers were retrieved by searching PubMed and Scopus
databases. A systematic approach was adopted when overviewing the
different PDE isoforms, taking into account details on brain localization,
downstream molecular mechanisms, and inhibitors currently under study,
according to available in vitro and in vivo data. In the context of drug repurposing, a section focusing on
PDE5 was introduced. Original computational studies were performed
to rationalize the emerging evidence that suggests the role of PDE5
inhibitors as multi-target agents against neurodegeneration.
Moreover, since such compounds must cross the blood–brain barrier
and reach inhibitory concentrations in the central nervous system
to exert their therapeutic activity, physicochemical parameters
were analyzed and discussed. Taken together, literature and computational
data suggest that some PDE5 inhibitors, such as tadalafil, represent
promising candidates.
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Affiliation(s)
- Giovanni Ribaudo
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy
| | - Alberto Ongaro
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy
| | - Giuseppe Zagotto
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy
| | - Maurizio Memo
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy
| | - Alessandra Gianoncelli
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy
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Bhandari S, Nuengchamnong N, Chaichamnong N, Seasong T, Ingkaninan K, Temkitthawon P. At-line LC-QTOF-MS micro-fractionation of Derris scandens (Roxb.) Benth, coupled to radioassay for the early identification of PDE5A1 inhibitors. PHYTOCHEMICAL ANALYSIS : PCA 2020; 31:297-305. [PMID: 31777141 DOI: 10.1002/pca.2895] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 09/25/2019] [Accepted: 09/27/2019] [Indexed: 06/10/2023]
Abstract
INTRODUCTION Chromatographic techniques coupled with bioassays are popularly used for the detection of bioactive compounds in natural products. In this study phytochemicals responsible for showing Phosphodiesterase type 5 (PDE5) inhibitory activity in Derris scandens were studied using at-line method. OBJECTIVE The objective of this study was to develop an at-line liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) micro-fractionation method for rapid separation and identification of PDE5A1 inhibitors in 95% ethanolic extract of D. scandens. METHODOLOGY Initially, the correlation between LC-MS and PDE5A1 inhibitory activity was studied using three concentrations of 1:1 mixture of sildenafil and derrisisoflavone A; PDE5A1 inhibitors. The mixture was separated by high-performance liquid chromatography (HPLC) column and the eluent was split into two flows in the ratio of 1:9. The major part was collected in a 96-well plate, in each well consecutively every 30 s. The minor part was fed into an electrospray ionisation (ESI)-QTOF-MS system. After subsequent solvent removal, the collected micro-fractions were subjected to radioassay to determine PDE5A1 inhibition. RESULTS The result showed, PDE5A1 inhibitory activities of the micro-fractions were observed in a dose response manner and found to be in agreement with an off-line study. Similarly, 95% ethanolic extract of D. scandens was subjected to the at-line LC-QTOF-MS micro-fractionation developed, resulting in separation and tentative identification of 25 compounds with PDE5A1 inhibitory activity. Most of the compounds contained prenylated isoflavone skeleton. Additionally, the active micro-fractions also showed selectivity on PDE5A1 over PDE6 and PDE1B. CONCLUSION Our results demonstrated that the at-line coupled LC-QTOF-MS micro-fractionation with PDE5A1 inhibitory assay is a valuable tool for identifying PDE5A1 inhibitors from complex extracts.
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Affiliation(s)
- Samjhana Bhandari
- Bioscreening Unit, Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmaceutical Sciences and Centre of Excellence for Innovation in Chemistry, Phitsanulok, Thailand
| | - Nitra Nuengchamnong
- Science Lab Centre, Faculty of Science, Naresuan University, Phitsanulok, Thailand
| | - Nattiya Chaichamnong
- Bioscreening Unit, Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmaceutical Sciences and Centre of Excellence for Innovation in Chemistry, Phitsanulok, Thailand
- Division of Applied Thai Traditional Medicine, Faculty of Public Health, Naresuan University, Phitsanulok, Thailand
| | - Tongchai Seasong
- Bioscreening Unit, Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmaceutical Sciences and Centre of Excellence for Innovation in Chemistry, Phitsanulok, Thailand
| | - Kornkanok Ingkaninan
- Bioscreening Unit, Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmaceutical Sciences and Centre of Excellence for Innovation in Chemistry, Phitsanulok, Thailand
| | - Prapapan Temkitthawon
- Bioscreening Unit, Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmaceutical Sciences and Centre of Excellence for Innovation in Chemistry, Phitsanulok, Thailand
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Tzoumas N, Farrah TE, Dhaun N, Webb DJ. Established and emerging therapeutic uses of PDE type 5 inhibitors in cardiovascular disease. Br J Pharmacol 2020; 177:5467-5488. [PMID: 31721165 PMCID: PMC7707100 DOI: 10.1111/bph.14920] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 10/15/2019] [Accepted: 10/21/2019] [Indexed: 12/21/2022] Open
Abstract
PDE type 5 inhibitors (PDE5Is), such as sildenafil, tadalafil and vardenafil, are a class of drugs used to prolong the physiological effects of NO/cGMP signalling in tissues through the inhibition of cGMP degradation. Although these agents were originally developed for the treatment of hypertension and angina, unanticipated side effects led to advances in the treatment of erectile dysfunction and, later, pulmonary arterial hypertension. In the last decade, accumulating evidence suggests that PDE5Is may confer a wider range of clinical benefits than was previously recognised. This has led to a broader interest in the cardiovascular therapeutic potential of PDE5Is, in conditions such as hypertension, myocardial infarction, stroke, peripheral arterial disease, chronic kidney disease and diabetes mellitus. Here, we review the pharmacological properties and established licensed uses of this class of drug, along with emerging therapeutic developments and possible future indications.
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Affiliation(s)
- Nikolaos Tzoumas
- British Heart Foundation/University Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.,Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, UK
| | - Tariq E Farrah
- British Heart Foundation/University Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Neeraj Dhaun
- British Heart Foundation/University Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - David J Webb
- British Heart Foundation/University Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
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Dar MI, Jan S, Reddy GL, Wani R, Syed M, Dar MJ, Sawant SD, Vishwakarma RA, Syed SH. Differentiation of human neuroblastoma cell line IMR-32 by sildenafil and its newly discovered analogue IS00384. Cell Signal 2019; 65:109425. [PMID: 31689507 DOI: 10.1016/j.cellsig.2019.109425] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 09/14/2019] [Accepted: 09/19/2019] [Indexed: 11/26/2022]
Abstract
Sildenafil, a phosphodiesterase-5 inhibitor is FDA approved drug against erectile dysfunction. It is currently undergoing many clinical trials, alone or in combinations against different diseases. Treatment of neural progenitor cells with sildenafil is known to regulate their basal cGMP levels and enhance neurogenesis and differentiation. cGMP as well as cAMP are known to play a central role in the maintenance, repair and remodelling of the nervous system. In the present study, we report the neurodifferentiation property of sildenafil in neuroblastoma cancer cell line IMR-32. Sildenafil was found to induce the formation of neurite outgrowths that were found expressing neuronal markers, such as NeuN, NF-H and βIII tubulin. IS00384, a recently discovered PDE5 inhibitor by our laboratory, was also found to induce neurodifferentiation of IMR-32 cells. The effect of IS00384 on differentiation was even more profound than sildenafil. Both the compounds were found to elevate and activate the Guanine nucleotide exchange factor C3G, which is a regulator of differentiation in IMR-32 cells. They were also found to elevate the levels of cGMP and activate the AMPK-ACC and PI3K-Akt signalling pathways. These pathways are known to play important role in cytoskeletal rearrangements necessary for differentiation. This study highlights the role of phosphodiesterases-5 in neurodifferentiation and use of sildenafil and IS00384 as small molecule tools to study the process of cellular differentiation.
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Affiliation(s)
- Mohd I Dar
- CSIR- Indian Institute of Integrative Medicine, Sanatnagar, Srinagar, Kashmir, India; Academy of Scientific and Innovative Research, India
| | - Suraya Jan
- CSIR- Indian Institute of Integrative Medicine, Sanatnagar, Srinagar, Kashmir, India; Academy of Scientific and Innovative Research, India
| | - G Lakshma Reddy
- Academy of Scientific and Innovative Research, India; Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India
| | - Rubiada Wani
- CSIR- Indian Institute of Integrative Medicine, Sanatnagar, Srinagar, Kashmir, India; Academy of Scientific and Innovative Research, India
| | - Mudassir Syed
- High Content Imaging Facility, CSIR-Indian Institute of Integrative Medicine, India
| | - Mohd J Dar
- Academy of Scientific and Innovative Research, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India
| | - Sanghapal D Sawant
- Academy of Scientific and Innovative Research, India; Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India
| | - Ram A Vishwakarma
- Academy of Scientific and Innovative Research, India; Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India
| | - Sajad H Syed
- CSIR- Indian Institute of Integrative Medicine, Sanatnagar, Srinagar, Kashmir, India; Academy of Scientific and Innovative Research, India.
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In Silico Mapping of Essential Residues in the Catalytic Domain of PDE5 Responsible for Stabilization of Its Commercial Inhibitors. Sci Pharm 2019. [DOI: 10.3390/scipharm87040029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Phosphodiesterase type 5 (PDE5) is an important enzyme associated with the hydrolysis of cyclic guanosine monophosphate (cGMP) to guanosine monophosphate (GMP). Due to the relevant role of second messenger cGMP as a mediator in many physiological processes, efforts have been converged to find a safe pharmacological approach, seeking a specific, selective and potent inhibitor of the PDE5 enzyme. There are five commercial drugs with potential for clinical use: tadalafil, sildenafil, avanafil, udenafil and vardenafil. Here, we applied molecular modeling to obtain different profiles of protein–ligand interactions by adopting distinct PDE5 structures, specifically PDBid:1XOZ and two extracted from molecular dynamics (MD) simulations. The results generated by molecular docking showed several possibilities for inhibitor interactions with the catalytic pocket. Tadalafil, sildenafil and vardenafil were clearly stabilized by Gln817 via a well-oriented hydrogen bond. Another set of different interactions, such as polar, hydrophobic, π-stacking, metal–ligand and electrostatic, were responsible for accommodating avanafil and udenafil. All of the ligands are discussed in detail with consideration of the distinct protein structures, and a profile of the probability of residue–ligand contact is suggested, with the most frequently observed being: Tyr612, His613, Ser661, Thr723, Asp724, Asp764, Leu765, Val782 and Phe786. The molecular interactions displayed herein confirm findings achieved by previous authors and also present new contacts. In addition, the discussion can help researchers obtain a molecular basis for planning new selective PDE5 inhibitors, as well as explain an inhibitor’s experimental assays by considering the specific interactions occurring at the catalytic site.
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Kim JN, Oh JJ, Park DS, Hong YK, Yu YD. Influence of Alcohol on Phosphodiesterase 5 inhibitors Use in Middle- to Old-Aged Men: A Comparative Study of Adverse Events. Sex Med 2019; 7:425-432. [PMID: 31444051 PMCID: PMC6963111 DOI: 10.1016/j.esxm.2019.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Revised: 07/22/2019] [Accepted: 07/28/2019] [Indexed: 11/01/2022] Open
Abstract
INTRODUCTION Some previous studies reported recreational use of phosphodiesterase type 5 (PDE-5) inhibitors by ingesting the medicine with alcohol in patients with erectile dysfunction, but the rate of misuse in general population has never been researched. AIM To investigate the frequency of concomitant alcohol consumption with PDE-5 inhibitors in the general male population. We secondarily analyzed the influence of alcohol on PDE-5 inhibitor. METHODS 325 men with erectile dysfunction (age 34-78) who received PDE-5 inhibitors at a single medical institution from January 2016-February 2018 were included in the study. All patients fulfilled a survey questionnaire assessing (i) average alcohol consumption amount, (ii) previous use of PDE-5 inhibitors with alcohol and purpose of concomitant alcohol use, (iii) and background knowledge about PDE-5 inhibitors' side effects. MAIN OUTCOMES MEASURES The main outcome measure was frequency of concomitant alcohol consumption with PDE-5 inhibitors in the general male population. RESULTS Overall 148 patients committed concomitant alcohol use (group 1), and 177 patients did not (group 2). No significant differences were observed between 2 groups regarding types of PDE-5 inhibitors used and underlying disease. Group 2 had significantly more patients with the correct knowledge concerning concomitant alcohol use than group 1 (24.9% vs 13.5%). Group 1 had more patients with average alcohol consumption >15 drinks/week (64.8% vs 14.1%). The reasons for concomitant alcohol use were curiosity (35.1%), enhancing sexual desire (27%) and recommendation from friends (16.9%). Group 1 showed significantly greater complications, including headache (23.6% vs 7.3%) and facial flushing (69.6% vs 12.4%), than group 2. 1 patient in group 1 experienced severe chest discomfort and underwent coronary artery angiography, but no severe obstructive lesion was observed. CONCLUSION 45.5% of middle- to old-age men committed concomitant use of PDE-5 inhibitor with alcohol because of recreational purpose, and this alcohol abuse might lead to severe complications, including chest discomfort and dizziness. Kim JN, Oh JJ, Park DS, et al. Influence of Alcohol on Phosphodiesterase 5 inhibitors Use in Middle- to Old-Aged Men: A Comparative Study of Adverse Events. Sex Med 2019;7:425-432.
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Affiliation(s)
- Jong Nyeong Kim
- Department of Urology, CHA Medical University, College of Medicine, Bundang CHA Hospital, Seongnam, Korea
| | - Jong Jin Oh
- Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Dong Soo Park
- Department of Urology, CHA Medical University, College of Medicine, Bundang CHA Hospital, Seongnam, Korea
| | - Young Kwon Hong
- Department of Urology, CHA Medical University, College of Medicine, Bundang CHA Hospital, Seongnam, Korea
| | - Young Dong Yu
- Department of Urology, CHA Medical University, College of Medicine, Bundang CHA Hospital, Seongnam, Korea.
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Carter EA, Lohse K, Sheel W, Koehle M. Sildenafil does not reliably improve exercise performance in hypoxia: a systematic review. BMJ Open Sport Exerc Med 2019; 5:e000526. [PMID: 31191974 PMCID: PMC6539183 DOI: 10.1136/bmjsem-2019-000526] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/21/2019] [Indexed: 11/05/2022] Open
Abstract
Objective Sildenafil is a pulmonary vasodilator that may reduce the decrement in endurance performance in moderate hypoxia. We assessed the efficacy of sildenafil to improve performance in hypoxia. Data sources/eligibility Criteria We systematically searched electronic databases (until August 2018) for randomised trials comparing sildenafil with placebo. We also examined the effect of sildenafil on pulmonary artery pressure (PAP), cardiac output (CO) and pulse oxygen saturation (SPO2) compared with placebo in hypoxia. Fourteen studies were included; 210 subjects received sildenafil 40, 50 or 100 mg/day. Results Sildenafil showed a large effect for decreasing PAP during exercise and at rest, a small effect for increasing CO during exercise and a moderate effect at rest, a moderate effect for increasing SPO2 and a small effect for improving performance. In a subgroup analysis, there was no statistically significant difference between 100 and 50 mg sildenafil dose on SPO2. Sildenafil had a moderate effect on increasing SPO2 and performance at terrestrial hypobaric altitude but only a small effect on both in normobaric hypoxia. Regression analysis showed that hypoxic dose (PO2) and metabolic rate do not account for a significant portion of the variance in effect size for sildenafil on PAP, CO, SPO2 and performance. Conclusion This meta-analysis indicates that sildenafil reduces PAP, has a moderate to small effect on CO and SPO2, and no effect on performance.
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Affiliation(s)
| | - Keith Lohse
- Health-Kinesiology-Recreation, University of Utah, Salt Lake City, Utah, USA
| | - William Sheel
- Kinesiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Michael Koehle
- Kinesiology, University of British Columbia, Vancouver, British Columbia, Canada.,Division of Sports Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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Jiang Z, Zheng X, Li Z, Pan S, Wang X, Zhang C, Li Z, Luo HB, Wu D, Cai X. 3D-QSAR modeling of Phosphodiesterase-5 inhibitors: evaluation and comparison of the receptor- and ligand-based alignments. Med Chem Res 2019. [DOI: 10.1007/s00044-019-02311-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Eskandar AM. Effect of sildenafil in the management of preoperative pulmonary hypertension. ALEXANDRIA JOURNAL OF MEDICINE 2019. [DOI: 10.1016/j.ajme.2013.04.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Affiliation(s)
- Ashraf M. Eskandar
- Department of Anesthesia and Surgical Intensive Care, Faculty of Medicine, Menoufiya University, Shibeen Elkoom, Egypt
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Treatment of pulmonary arterial hypertension: A review of drugs available for advanced therapy. Afr J Thorac Crit Care Med 2019; 25. [PMID: 34286246 PMCID: PMC8279001 DOI: 10.7196/sarj.2019.v25i1.236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/07/2019] [Indexed: 11/28/2022] Open
Abstract
Pulmonary hypertension (PH) has traditionally been considered a rare disease with a uniformly poor prognosis. However, this was prior
to the introduction of advanced therapies for this condition, and more recent registries in the treatment era have shown 5-year survival
rates of up to 65%. Prior to 2000, there was only one licensed therapy for pulmonary arterial hypertension (PAH); less than 20 years later,
the US Food and Drug Administration has approved 14 different medications for PAH. This review aims to summarise for the general
pulmonologist the evidence for the current internationally available advanced therapies for PAH (World Health Organization Group I
disease), which is characterised haemodynamically by the presence of precapillary PH in the absence of another cause. The benefit of these
agents, either alone or in combinations, is now undisputed and their use is advocated in all current international guidelines for PAH. The
improvement in survival of patients with PAH over the concurrent timeline emphasises the importance both of the availability and usage of
effective therapies and of patients being seen in specialist centres, where physicians are familiar with using these therapies.
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Hoenicka M, Golovchenko S, Englert L, Spaeth M, Shoshiashvili L, Großer C, Hofmann HS, Ried M. Combination Therapy of Pulmonary Arterial Hypertension with Vardenafil and Macitentan Assessed in a Human Ex Vivo Model. Cardiovasc Drugs Ther 2019; 33:287-295. [DOI: 10.1007/s10557-019-06868-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Ahmed NS. Tadalafil: 15 years' journey in male erectile dysfunction and beyond. Drug Dev Res 2018; 80:683-701. [PMID: 30548639 DOI: 10.1002/ddr.21493] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 10/31/2018] [Accepted: 11/01/2018] [Indexed: 12/17/2022]
Abstract
Hit, Lead & Candidate Discovery Tadalafil, Cialis, Eli Lilly & Co./ICOS, (6R,12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6] pyrido[3,4-b]indole-1,4-dione, was first discovered in 2003. It was reported to have high diastereospecificity for phosphodiesterase 5 (PDE5) inhibitions. The cis-(6R, 12aR) enantiomer is the most active enantiomer. Tadalafil showed PDE5 inhibition with IC50 = 5 nM. It possesses high selectivity for PDE5 versus PDE1-4 and PDE6. Tadalafil is more selective to PDE5 against PDE6 whereas sildenafil, another commercially available PDE5 inhibitor shows similar potencies to inhibit PDE5 and PDE6. Tadalafil is used for the treatment of male erectile dysfunction (MED), prostatic benign hyperplasia (PBH) signs and symptoms, and pulmonary arterial hypertension (PAH). Adcirca, another name for tadalafil, is used to treat PAH and improve exercise capacity. Recent clinical studies suggest the use of tadalafil for nonurological applications, including circulatory disorders (ischemia injury, myocardial infarction, cardiac hypertrophy, cardiomyopathy, heart failure, and stroke), neurodegenerative disorders, and cognitive impairment conditions. This review discusses tadalafil and its analogues reported in the past 15 years. It discusses synthetic pathways, structural activity relationships, existing and future pharmacological indications of tadalafil and its analogues. This work can help medicinal chemists developing novel PDE5 inhibitors with wider therapeutic indications.
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Affiliation(s)
- Nermin S Ahmed
- Faculty of Pharmacy and Biotechnology, Department of Pharmaceutical Chemistry, German University in Cairo, Cairo, Egypt
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Li EA, Xi W, Han YS, Brozovich FV. Phosphodiesterase expression in the normal and failing heart. Arch Biochem Biophys 2018; 662:160-168. [PMID: 30550727 DOI: 10.1016/j.abb.2018.12.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 12/07/2018] [Accepted: 12/10/2018] [Indexed: 01/09/2023]
Abstract
The number of patients with heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) is increasing, and for HFpEF, no therapies have clinical benefit. It has been hypothesized that PKG attenuates pathological remodelling, and increasing cGMP would be beneficial for patients with HF. However, neither the RELAX nor NEAT-HFpEF trial showed benefit. But there is still enthusiasm for increasing cGMP in patients with HF, which highlight the need to determine the expression of PDEs in cardiac muscle. This study used immunoblotting to examine the expression of the PDEs that have been suggested to be targets for therapy of HF in both canines (normal and HFpEF) and humans (normal and HFrEF). Our results demonstrate PDE1C and PDE3A are expressed in cardiac muscle, but we could not detect the expression of PDE2A, PDE5A, PDE7A and PDE9A in cardiac tissue lysates from either normal or failing hearts. Thus, one should not expect a clinical benefit for a therapy targeting these PDEs in heart failure, which highlights the importance of rigorous demonstration of the target of therapy prior to undertaking a clinical trial.
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Affiliation(s)
- Edwin A Li
- Department of Cardiovascular Disease, Mayo Medical School, Rochester, MN, 55905, USA
| | - Wang Xi
- Biomedical Engineering and Physiology, Mayo Medical School, Rochester, MN, 55905, USA
| | - Young Soo Han
- Biomedical Engineering and Physiology, Mayo Medical School, Rochester, MN, 55905, USA
| | - Frank V Brozovich
- Department of Cardiovascular Disease, Mayo Medical School, Rochester, MN, 55905, USA.
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Schaffner D, Lazaro A, Deibert P, Hasselblatt P, Stoll P, Fauth L, Baumstark MW, Merfort I, Schmitt-Graeff A, Kreisel W. Analysis of the nitric oxide-cyclic guanosine monophosphate pathway in experimental liver cirrhosis suggests phosphodiesterase-5 as potential target to treat portal hypertension. World J Gastroenterol 2018; 24:4356-4368. [PMID: 30344420 PMCID: PMC6189851 DOI: 10.3748/wjg.v24.i38.4356] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 08/03/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the potential effect of inhibitors of phosphodiesterase-5 (PDE-5) for therapy of portal hypertension in liver cirrhosis. METHODS In the rat model of thioacetamide-induced liver fibrosis/cirrhosis the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway was investigated. Expression and localization of PDE-5, the enzyme that converts vasodilating cGMP into inactive 5'-GMP, was in the focus of the study. Hepatic gene expression of key components of the NO-cGMP pathway was determined by qRT-PCR: Endothelial NO synthase (eNOS), inducible NO synthase (iNOS), soluble guanylate cyclase subunits α1 and β1 (sGCa1, sGCb1), and PDE-5. Hepatic PDE-5 protein expression and localization were detected by immunohistochemistry. Serum cGMP concentrations were measured using ELISA. Acute effects of the PDE-5 inhibitor Sildenafil (0.1 mg/kg or 1.0 mg/kg) on portal and systemic hemodynamics were investigated using pressure transducers. RESULTS Hepatic gene expression of eNOS (2.2-fold; P = 0.003), sGCa1 (1.7-fold; P = 0.003), sGCb1 (3.0-fold; P = 0.003), and PDE-5 (11-fold; P = 0.003) was increased in cirrhotic livers compared to healthy livers. Overexpression of PDE-5 (7.7-fold; P = 0.006) was less pronounced in fibrotic livers. iNOS expression was only detected in fibrotic and cirrhotic livers. In healthy liver, PDE-5 protein was localized primarily in zone 3 hepatocytes and to a lesser extent in perisinusoidal cells. This zonation was disturbed in cirrhosis: PDE-5 protein expression in perisinusoidal cells was induced approximately 8-fold. In addition, PDE-5-expressing cells were also found in fibrous septa. Serum cGMP concentrations were reduced in rats with cirrhotic livers by approximately 40%. Inhibition of PDE-5 by Sildenafil caused a significant increase in serum cGMP concentrations [+ 64% in healthy rats (P = 0.024), + 85% in cirrhotic rats (P = 0.018)]. Concomitantly, the portal venous pressure was reduced by 19% in rats with liver cirrhosis. CONCLUSION Overexpression and abrogated zonation of PDE-5 likely contribute to the pathogenesis of cirrhotic portal hypertension. PDE-5 inhibition may therefore be a reasonable therapeutic approach for portal hypertension.
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MESH Headings
- Animals
- Cyclic GMP/blood
- Cyclic GMP/metabolism
- Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism
- Guanosine Monophosphate/metabolism
- Humans
- Hypertension, Portal/blood
- Hypertension, Portal/drug therapy
- Hypertension, Portal/etiology
- Hypertension, Portal/pathology
- Liver/drug effects
- Liver/metabolism
- Liver/pathology
- Liver Cirrhosis, Experimental/blood
- Liver Cirrhosis, Experimental/chemically induced
- Liver Cirrhosis, Experimental/complications
- Liver Cirrhosis, Experimental/pathology
- Male
- Nitric Oxide/metabolism
- Nitric Oxide Synthase/metabolism
- Phosphodiesterase 5 Inhibitors/pharmacology
- Phosphodiesterase 5 Inhibitors/therapeutic use
- Rats
- Rats, Sprague-Dawley
- Rats, Wistar
- Signal Transduction/drug effects
- Sildenafil Citrate/pharmacology
- Sildenafil Citrate/therapeutic use
- Thioacetamide/toxicity
- Treatment Outcome
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Affiliation(s)
- Denise Schaffner
- Institute for Exercise-und Occupational Medicine, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, Freiburg 79104, Germany
| | - Adhara Lazaro
- Institute for Exercise-und Occupational Medicine, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany
| | - Peter Deibert
- Institute for Exercise-und Occupational Medicine, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany
| | - Peter Hasselblatt
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany
| | - Patrick Stoll
- Anaesthesiological Practice, Freiburg 79104, Germany
| | - Lisa Fauth
- Institute of Clinical Pathology, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany
| | - Manfred W Baumstark
- Institute for Exercise-und Occupational Medicine, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany
| | - Irmgard Merfort
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, Freiburg 79104, Germany
| | - Annette Schmitt-Graeff
- Institute of Clinical Pathology, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany
| | - Wolfgang Kreisel
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany
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Lyle MA, Brozovich FV. HFpEF, a Disease of the Vasculature: A Closer Look at the Other Half. Mayo Clin Proc 2018; 93:1305-1314. [PMID: 30064827 DOI: 10.1016/j.mayocp.2018.05.001] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 04/12/2018] [Accepted: 05/04/2018] [Indexed: 12/31/2022]
Abstract
Patients with heart failure are commonly divided into those with reduced ejection fraction (EF<40%) and those with preserved ejection fraction (HFpEF; EF>50%). For heart failure with reduced EF, a number of therapies have been found to improve patient morbidity and mortality, and treatment is guideline based. However for patients with HFpEF, no treatment has been found to have clinical benefit. To objectively assess treatments for HFpEF, a comprehensive PubMed literature search was performed using the terms HFpEF, heart failure, smooth muscle, myosin, myosin phosphatase, and PKG (up to December 31, 2017), with an unbiased focus on pathophysiology, cell signaling, and therapy. This review provides evidence that could explain the lack of clinical benefit in treating patients with HFpEF with sildenafil and long-acting nitrates. Furthermore, the review highlights the vascular abnormalities present in patients with HFpEF, and these abnormalities of the vasculature could potentially contribute to the pathophysiology of HFpEF. Thus, focusing on HFpEF as a vascular disease could result in the development of novel and effective treatment paradigms.
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Affiliation(s)
- Melissa A Lyle
- Department of Cadiovascular Diseases, Mayo Clinic College of Medicine and Science, Rochester, MN
| | - Frank V Brozovich
- Department of Cadiovascular Diseases, Mayo Clinic College of Medicine and Science, Rochester, MN.
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Andersson KE. PDE5 inhibitors - pharmacology and clinical applications 20 years after sildenafil discovery. Br J Pharmacol 2018; 175:2554-2565. [PMID: 29667180 DOI: 10.1111/bph.14205] [Citation(s) in RCA: 194] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 03/01/2018] [Accepted: 03/05/2018] [Indexed: 11/28/2022] Open
Abstract
The discovery of the nitric oxide/cGMP pathway was the basis for our understanding of many normal physiological functions and the pathophysiology of several diseases. Since the discovery and introduction of sildenafil, inhibitors of PDE5 have been the first-line therapy for erectile dysfunction (ED). The success of sildenafil in the treatment of ED stimulated research in the field of PDE5 inhibition and led to many new applications, such as treatment of lower urinary symptoms, and pulmonary arterial hypertension, which are now approved indications. However, PDE5 inhibitors have also been used in several other disorders not discussed in this review, and the fields of clinical use are increasing. In the present review, the pharmacological basis of the NO/cGMP pathway and the rationale and clinical use of PDE5 inhibitors in different diseases are discussed.
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Affiliation(s)
- K-E Andersson
- Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA.,Institute of Laboratory Medicine, Lund University, 223 62, Lund, Sweden
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48
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3,7-Bis(2-hydroxyethyl)icaritin, a potent inhibitor of phosphodiesterase-5, prevents monocrotaline-induced pulmonary arterial hypertension via NO/cGMP activation in rats. Eur J Pharmacol 2018; 829:102-111. [PMID: 29665366 DOI: 10.1016/j.ejphar.2018.04.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 04/10/2018] [Accepted: 04/13/2018] [Indexed: 12/22/2022]
Abstract
Pulmonary arterial hypertension (PAH) is a chronic progressive disease which leads to elevated pulmonary arterial pressure and right heart failure. 3,7-Bis(2-hydroxyethyl)icaritin (ICT), an icariin derivatives, was reported to have potent inhibitory activity on phosphodiesterase type 5 (PDE5) which plays a crucial role in the pathogenesis of PAH. The present study was designed to investigate the effects of ICT on monocrotaline (MCT)-induced PAH rat model and reveal the underlying mechanism. MCT-induced PAH rat models were established with intragastric administration of ICT (10, 20, 40 mg/kg/d), Icariin (ICA) (40 mg/kg/d) and Sildenafil (25 mg/kg/d). The mean pulmonary arterial pressure (mPAP) and right ventricle hypertrophy index (RVHI) were measured. Pulmonary artery remodeling was assessed by H&E staining. Blood and lung tissue were collected to evaluate the level of endothelin 1 (ET-1), nitric oxide (NO), and cyclic guanosine monophosphate (cGMP). The expressions endothelial nitric oxide synthase (eNOS) and PDE5A in lung tissues were determined by Western blot analysis. The results showed that ICT reduced RVHI and mPAP, and reversed lung vascular remodeling in rats with MCT-induced PAH. ICT also reversed MCT-induced ET-1 elevation, NO and cGMP reduction in serum or lung tissue. Moreover, ICT administration significantly induced eNOS activation and PDE5A inhibition. ICT with lower dose had better effects than ICA. In summary, ICT is more effective in preventing MCT-induced PAH in rats via NO/cGMP activation compared with ICA. These findings demonstrate a novel mechanism of the action of ICT that may have value in prevention of PAH.
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Bhat L, Hawkinson J, Cantillon M, Reddy DG, Bhat SR, Laurent CE, Bouchard A, Biernat M, Salvail D. Evaluation of the effects of RP5063, a novel, multimodal, serotonin receptor modulator, as single-agent therapy and co-administrated with sildenafil, bosentan, and treprostinil in a monocrotaline-induced pulmonary arterial hypertension rat model. Eur J Pharmacol 2018; 827:159-166. [PMID: 29453947 DOI: 10.1016/j.ejphar.2018.02.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 02/08/2018] [Accepted: 02/09/2018] [Indexed: 12/18/2022]
Abstract
Pulmonary arterial hypertension (PAH), a condition that is defined by pulmonary vasculature constriction and remodeling, involves dysfunctional signaling of the serotonin (5-HT) receptors, 5-HT2A/2B/7. In a rat model of monocrotaline (MCT)-induced PAH, the effectiveness of RP5063 (RP), a dopamine and 5-HT receptor modulator, was evaluated as monotherapy and as an adjunct to standard PAH treatments. After a single 60 mg/kg dose of MCT, rats received vehicle (MCT+Veh; gavage twice-daily [b.i.d.]), RP (10 mg/kg; gavage b.i.d.), bosentan (B; 100 mg/kg; gavage BID), sildenafil (S; 50 mg/kg; gavage, BID), treprostinil (T; 100 ng/kg/min over 24 h intravenous), RP+B, RP+S, and RP+T for 28 days. Single-agent RP limited the functional and structural effects of PAH seen in the MCT+Veh group, with significant improvements in pulmonary hemodynamics, right ventricular (RV) hypertrophy, SO2, and pulmonary blood vessel structural changes. These effects appeared comparable with those associated with B, S, and T. Adjunctive RP treatment resulted in significantly lower mean pulmonary arterial pressures, RV systolic pressure. It also improved SO2 measurements, as compared with MCT+Veh (P < 0.05), and diastolic pulmonary artery pressure (P < 0.05), as compared with single-agent B and S therapy (Bonferroni method adjusting for multiplicity). RP+S appeared to show the most consistent and extensive effects on pulmonary hemodynamics, respiratory parameters, and histopathologic changes. These results corroborate earlier preclinical findings supporting the efficacy of single-agent RP in PAH. RP, as mono and adjunctive therapy compared with induced-control, mitigated the functional and structural effects of MCT-induced PAH.
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Affiliation(s)
| | - Jon Hawkinson
- Institute for Therapeutics Discovery & Development and Department of Medicinal Chemistry, University of Minnesota, Minnesota, MN, USA
| | | | | | - Seema R Bhat
- Reviva Pharmaceuticals, Inc., Sunnyvale, CA, USA
| | | | | | | | - Dany Salvail
- IPS Therapeutique Inc., Sherbrooke, Quebec, Canada
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Akabane R, Sato T, Sakatani A, Miyagawa Y, Tazaki H, Takemura N. Pharmacokinetics of single-dose sildenafil administered orally in clinically healthy dogs: Effect of feeding and dose proportionality. J Vet Pharmacol Ther 2018; 41:457-462. [DOI: 10.1111/jvp.12487] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 01/02/2018] [Indexed: 12/01/2022]
Affiliation(s)
- R. Akabane
- Laboratory of Veterinary Internal Medicine II; School of Veterinary Medicine; Nippon Veterinary and Life Science University; Musashino-shi Japan
| | - T. Sato
- Laboratory of Biomolecular Chemistry; School of Veterinary Medicine; Nippon Veterinary and Life Science University; Musashino-shi Japan
| | - A. Sakatani
- Laboratory of Veterinary Internal Medicine II; School of Veterinary Medicine; Nippon Veterinary and Life Science University; Musashino-shi Japan
| | - Y. Miyagawa
- Laboratory of Veterinary Internal Medicine II; School of Veterinary Medicine; Nippon Veterinary and Life Science University; Musashino-shi Japan
| | - H. Tazaki
- Laboratory of Biomolecular Chemistry; School of Veterinary Medicine; Nippon Veterinary and Life Science University; Musashino-shi Japan
| | - N. Takemura
- Laboratory of Veterinary Internal Medicine II; School of Veterinary Medicine; Nippon Veterinary and Life Science University; Musashino-shi Japan
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