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Kots AY, Bian K. Regulation and Pharmacology of the Cyclic GMP and Nitric Oxide Pathway in Embryonic and Adult Stem Cells. Cells 2024; 13:2008. [PMID: 39682756 PMCID: PMC11639989 DOI: 10.3390/cells13232008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/03/2024] [Accepted: 12/03/2024] [Indexed: 12/18/2024] Open
Abstract
This review summarizes recent advances in understanding the role of the nitric oxide (NO) and cyclic GMP (cGMP) pathway in stem cells. The levels of expression of various components of the pathway are changed during the differentiation of pluripotent embryonic stem cells. In undifferentiated stem cells, NO regulates self-renewal and survival predominantly through cGMP-independent mechanisms. Natriuretic peptides influence the growth of undifferentiated stem cells by activating particulate isoforms of guanylyl cyclases in a cGMP-mediated manner. The differentiation, recruitment, survival, migration, and homing of partially differentiated precursor cells of various types are sensitive to regulation by endogenous levels of NO and natriuretic peptides produced by stem cells, within surrounding tissues, and by the application of various pharmacological agents known to influence the cGMP pathway. Numerous drugs and formulations target various components of the cGMP pathway to influence the therapeutic efficacy of stem cell-based therapies. Thus, pharmacological manipulation of the cGMP pathway in stem cells can be potentially used to develop novel strategies in regenerative medicine.
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Affiliation(s)
- Alexander Y. Kots
- Veteran Affairs Palo Alto Health Care System, US Department of Veteran Affairs, Palo Alto, CA 90304, USA
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Peng H, Zhang H, Xin S, Li H, Liu X, Wang T, Liu J, Zhang Y, Song W. Associations between Erectile Dysfunction and Vascular Parameters: A Systematic Review and Meta-Analysis. World J Mens Health 2024; 42:712-726. [PMID: 38311372 PMCID: PMC11439810 DOI: 10.5534/wjmh.230192] [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: 07/25/2023] [Revised: 09/13/2023] [Accepted: 10/03/2023] [Indexed: 02/10/2024] Open
Abstract
PURPOSE Erectile dysfunction (ED) is associated with several vascular disorders, but the associations between ED and vascular parameters are still unclear. MATERIALS AND METHODS We analyzed and synthesized a comprehensive range of studies from PubMed, Web of Science, and Scopus regarding the associations between ED and the following measures: ankle-brachial index (ABI), pulse wave velocity (PWV), intima-media thickness (IMT), nitrate-mediated dilation (NMD), flow-mediated dilation (FMD), augmentation index (AI), endothelial progenitor cells (EPCs) and other vascular parameters. Subgroup analysis was conducted according to specific types of parameters. Study quality was assessed by using the Newcastle-Ottawa Scale. Sensitivity analysis was conducted to confirm the robustness of the pooled results. RESULTS Fifty-seven studies with 7,312 individuals were included. Twenty-eight studies were considered to be high-quality. ED patients had a 0.11 mm higher IMT (95% confidence interval [CI]: 0.07, 0.15), a 2.86% lower FMD (95% CI: -3.56, -2.17), a 2.34% lower NMD (95% CI: -3.37, -1.31), a 2.83% higher AI (95% CI: 0.02, 5.63), a 1.11 m/s higher PWV (95% CI: 0.01, 2.21), and a 0.72% lower percentage of EPCs (95% CI: -1.19, -0.24) compared to those without ED. However, ABI was similar between ED patients and non-ED individuals. According to sensitivity analysis, the pooled results were robust. CONCLUSIONS Our study confirmed the associations between ED and several vascular parameters and highlighted the importance of prevention and management of vascular and endothelial dysfunction in ED patients.
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Affiliation(s)
- Hao Peng
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- The Second Clinical School, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hanlin Zhang
- The First Clinical School, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sheng Xin
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hao Li
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaming Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jihong Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yucong Zhang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Wen Song
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Li L, Zhang Y, Ma M, Liu F, Shang Y, Yuan Q, Li X, Ju B. Does erectile dysfunction predict cardiovascular risk? A cross-sectional study of clinical characteristics in patients with erectile dysfunction combined with coronary heart disease. Front Cardiovasc Med 2024; 11:1341819. [PMID: 38562188 PMCID: PMC10984325 DOI: 10.3389/fcvm.2024.1341819] [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: 11/21/2023] [Accepted: 02/20/2024] [Indexed: 04/04/2024] Open
Abstract
Background Erectile Dysfunction (ED) is a common sexual dysfunction in men who are unable to consistently obtain and maintain sufficient penile erection to accomplish a satisfactory sexual life. ED is currently considered to be a predictor of cardiovascular disease (CVD), but few studies have observed the association between ED and clinical features of coronary heart disease (CHD). An investigation of the association between ED and clinical characteristics of CHD was carried out using a cross-sectional study design. Methods This cross-sectional single-center study was conducted in the Department of Cardiology and included 248 patients. Associations between patients' general information, underlying disease information, coronary heart disease information, and ED severity were statistically and analytically analyzed using SPSS 26.0 software. Patients with comparable clinical characteristics were grouped together using K-means clustering. Finally, ordered logistic regression analysis was performed for general and underlying disease information. Results In the comparison of general data, age, education, and weekly exercise were associated with the distribution of ED severity. In the comparison of underlying disease information, the number of underlying diseases, hypertension, diabetes, hyperlipidemia, anxiety state, and depressive state were associated with the distribution of ED severity. In the comparison of CHD information, the degree of ED severity was associated with CHD subtypes, lesion sites, number of stenoses, degree of stenosis, and interventional interventions. The time from ED to CHD onset was associated with the subtypes of CHD and the number of stenoses. We clustered the main characteristics of low-risk and high-risk patients and ordered logistic regression analysis found that BMI, smoking, alcoholism, number of underlying diseases, diabetes, anxiety state, and depression state were all risk factors for CHD severity (P < 0.05); the higher the value of the above factors, the more severe the degree of CHD. Age was a protective factor for CHD severity; the younger the patient, the lower the likelihood of myocardial infarction. Conclusion ED severity and the time from ED to CHD onset may be predictive of coronary heart disease severity. Reducing smoking and alcohol consumption, maintaining a healthy body weight, and regular physical activity are important in preventing CVD in ED patients.
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Affiliation(s)
- Luyu Li
- The First School of Clinical Medicine, The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yongtao Zhang
- The First School of Clinical Medicine, The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Miaomiao Ma
- The First School of Clinical Medicine, The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Feng Liu
- The First School of Clinical Medicine, The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yihan Shang
- The First School of Clinical Medicine, The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Quan Yuan
- The First School of Clinical Medicine, The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Xiao Li
- Department of Andrology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Baojun Ju
- Department of Andrology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
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Saltzman RG, Golan R, Masterson TA, Sathe A, Ramasamy R. Restorative therapy clinical trials for erectile dysfunction: a scoping review of endpoint measures. Int J Impot Res 2023; 35:720-724. [PMID: 36068326 DOI: 10.1038/s41443-022-00610-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 08/18/2022] [Accepted: 08/23/2022] [Indexed: 11/08/2022]
Abstract
Given the lack of regulatory approval for restorative therapies for the treatment of erectile dysfunction, we hypothesized that clinical trials would vary in methodology and endpoint measurements. Our objective was to analyze methodological approaches and outcome measures of clinical trials evaluating restorative therapies for erectile dysfunction. Data was extracted from clinicaltrials.gov on trials which contained the keywords "erectile dysfunction". We evaluated trials initiated between 2004 and 2021 which listed a restorative therapy intervention. We identified 95 trials investigating energy-based/shockwave therapies (60/95), stem cell therapies (25/95), platelet-based therapies (6/95), and others (4/95). Only 41.1% of the trials evaluated safety. The most common efficacy endpoint was International Index of Erectile Function and Sexual Health Inventory for Men, and only 29.5% utilized penile Doppler. Thirty (31.6%) trials had been completed yet only 3 (3.2%) have published results. We found substantial heterogeneity in methodological approach in the trials. Subjective measures of erectile function were commonly reported, but definitions of inclusion criteria and objective outcome measures were inconsistent. These results provide a basis for the design of future clinical trials to improve the quality of trial data and aid in the development of standardized criteria for erectile dysfunction clinical trials.
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Affiliation(s)
- Russell G Saltzman
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Roei Golan
- Florida State University College of Medicine, Tallahassee, FL, USA
| | - Thomas A Masterson
- Desai Sethi Urology Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Aditya Sathe
- University of Tennessee Health Science Center College of Medicine, Memphis, TN, USA
| | - Ranjith Ramasamy
- Desai Sethi Urology Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
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Pham T, Butler A, Weideman RA, Annaswamy TM. Phosphodiesterase 5 Inhibitor Use in Patients Undergoing Decompression Surgery for Lumbar Spinal Stenosis. Am J Phys Med Rehabil 2022; 101:341-347. [PMID: 34121069 DOI: 10.1097/phm.0000000000001821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVE Our objectives were to explore the association between phosphodiesterase 5 inhibitor use and lumbar decompression surgery by evaluating the prevalence of lumbar decompression surgery in a treatment group of patients with lumbar spinal stenosis compared with a control group. DESIGN We performed database review and extracted data including lumbar decompression surgery prevalence, phosphodiesterase 5 inhibitor dosage, and fill dates. Treatment group was defined as those with phosphodiesterase 5 inhibitor fill dates of less than 30 days before surgery, and control group was defined as those with phosphodiesterase 5 inhibitor fill dates at any other time. Lumbar decompression surgery prevalence rates for both groups were calculated. RESULTS Our study found 599 lumbar spinal stenosis patients who were prescribed phosphodiesterase 5 inhibitor. Three hundred thirty-eight underwent lumbar decompression surgery. Of these, 71 (21%) filled their prescription of less than 30 days before surgery, whereas 267 (79%) filled their prescription during a different period. The majority (94.6%) of surgical patients received decompression at two or more spinal levels. CONCLUSIONS Prevalence of lumbar decompression surgery for lumbar spinal stenosis was significantly lower in patients in the treatment group on phosphodiesterase 5 inhibitor therapy compared with the control group. Among many potential explanations, the vasodilatory effect of phosphodiesterase 5 inhibitor may have contributed to a lower surgical rate. This is the first study to explore this novel association. Future prospective studies are necessary to better define the utility of phosphodiesterase 5 inhibitor in lumbar spinal stenosis.
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Affiliation(s)
- Tri Pham
- From the University of Texas Southwestern Medical Center, Dallas, Texas (TP); University of Cincinnati College of Medicine, Cincinnati, Ohio (AB); Pharmacy Service, VA North Texas Health Care System, Dallas, Texas (RAW); Physical Medicine and Rehabilitation Service, VA North Texas Health Care System, Dallas, Texas (TMA); and Department of Physical Medicine and Rehabilitation, University of Texas Southwestern Medical Center, Dallas, Texas (TMA)
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Blanco-Rivero J, Xavier FE. Therapeutic Potential of Phosphodiesterase Inhibitors for Endothelial Dysfunction- Related Diseases. Curr Pharm Des 2021; 26:3633-3651. [PMID: 32242780 DOI: 10.2174/1381612826666200403172736] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 02/08/2020] [Indexed: 02/08/2023]
Abstract
Cardiovascular diseases (CVD) are considered a major health problem worldwide, being the main cause of mortality in developing and developed countries. Endothelial dysfunction, characterized by a decline in nitric oxide production and/or bioavailability, increased oxidative stress, decreased prostacyclin levels, and a reduction of endothelium-derived hyperpolarizing factor is considered an important prognostic indicator of various CVD. Changes in cyclic nucleotides production and/ or signalling, such as guanosine 3', 5'-monophosphate (cGMP) and adenosine 3', 5'-monophosphate (cAMP), also accompany many vascular disorders that course with altered endothelial function. Phosphodiesterases (PDE) are metallophosphohydrolases that catalyse cAMP and cGMP hydrolysis, thereby terminating the cyclic nucleotide-dependent signalling. The development of drugs that selectively block the activity of specific PDE families remains of great interest to the research, clinical and pharmaceutical industries. In the present review, we will discuss the effects of PDE inhibitors on CVD related to altered endothelial function, such as atherosclerosis, diabetes mellitus, arterial hypertension, stroke, aging and cirrhosis. Multiple evidences suggest that PDEs inhibition represents an attractive medical approach for the treatment of endothelial dysfunction-related diseases. Selective PDE inhibitors, especially PDE3 and PDE5 inhibitors are proposed to increase vascular NO levels by increasing antioxidant status or endothelial nitric oxide synthase expression and activation and to improve the morphological architecture of the endothelial surface. Thereby, selective PDE inhibitors can improve the endothelial function in various CVD, increasing the evidence that these drugs are potential treatment strategies for vascular dysfunction and reinforcing their potential role as an adjuvant in the pharmacotherapy of CVD.
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Affiliation(s)
- Javier Blanco-Rivero
- Departamento de Fisiologia, Facultad de Medicina, Universidad Autonoma de Madrid, Madrid, Spain
| | - Fabiano E Xavier
- Departamento de Fisiologia e Farmacologia, Centro de Biociencias, Universidade Federal de Pernambuco, Recife, Brazil
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Tentolouris A, Eleftheriadou I, Tzeravini E, Tsilingiris D, Paschou SA, Siasos G, Tentolouris N. Endothelium as a Therapeutic Target in Diabetes Mellitus: From Basic Mechanisms to Clinical Practice. Curr Med Chem 2020; 27:1089-1131. [PMID: 30663560 DOI: 10.2174/0929867326666190119154152] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 12/28/2018] [Accepted: 01/09/2019] [Indexed: 12/12/2022]
Abstract
Endothelium plays an essential role in human homeostasis by regulating arterial blood pressure, distributing nutrients and hormones as well as providing a smooth surface that modulates coagulation, fibrinolysis and inflammation. Endothelial dysfunction is present in Diabetes Mellitus (DM) and contributes to the development and progression of macrovascular disease, while it is also associated with most of the microvascular complications such as diabetic retinopathy, nephropathy and neuropathy. Hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia are the main factors involved in the pathogenesis of endothelial dysfunction. Regarding antidiabetic medication, metformin, gliclazide, pioglitazone, exenatide and dapagliflozin exert a beneficial effect on Endothelial Function (EF); glimepiride and glibenclamide, dipeptidyl peptidase-4 inhibitors and liraglutide have a neutral effect, while studies examining the effect of insulin analogues, empagliflozin and canagliflozin on EF are limited. In terms of lipid-lowering medication, statins improve EF in subjects with DM, while data from short-term trials suggest that fenofibrate improves EF; ezetimibe also improves EF but further studies are required in people with DM. The effect of acetylsalicylic acid on EF is dose-dependent and lower doses improve EF while higher ones do not. Clopidogrel improves EF, but more studies in subjects with DM are required. Furthermore, angiotensin- converting-enzyme inhibitors /angiotensin II receptor blockers improve EF. Phosphodiesterase type 5 inhibitors improve EF locally in the corpus cavernosum. Finally, cilostazol exerts favorable effect on EF, nevertheless, more data in people with DM are required.
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Affiliation(s)
- Anastasios Tentolouris
- Diabetes Center, 1st Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Ioanna Eleftheriadou
- Diabetes Center, 1st Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Evangelia Tzeravini
- Diabetes Center, 1st Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Dimitrios Tsilingiris
- Diabetes Center, 1st Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Stavroula A Paschou
- Diabetes Center, 1st Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Gerasimos Siasos
- First Department of Cardiology, Hippokration Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Nikolaos Tentolouris
- Diabetes Center, 1st Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
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Accardo G, Amoresano Paglionico V, Di Fraia R, Cittadini A, Salzano A, Esposito D, De Bellis A, Pasquali D. Management of cardiovascular complications in Klinefelter syndrome patients. Expert Rev Endocrinol Metab 2019; 14:145-152. [PMID: 30793993 DOI: 10.1080/17446651.2019.1584036] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 02/14/2019] [Indexed: 10/27/2022]
Abstract
INTRODUCTION Klinefelter syndrome (KS), also known as 47, XXY, shows increased mortality when compared with mortality rates among the general population. Cardiovascular, hemostatic, metabolic diseases are implicated. Moreover, cardiac congenital anomalies in KS can contribute to the increase in mortality. AREAS COVERED In this study, we have systematically reviewed the relationships between KS and the cardiovascular system and the management of cardiovascular complication. In summary, patients with KS display increased cardiovascular risk profile, characterized by increased prevalence of metabolic alterations including dyslipidemia, diabetes mellitus (DM), and abnormalities in biomarkers of cardiovascular disease. KS subjects are characterized by subclinical abnormalities in endothelial function and in left ventricular (LV) systolic and diastolic function, which - when associated with chronotropic incompetence - may negatively influence cardiopulmonary performance. Moreover, KS patients appear to be at a higher risk for cardiovascular disease, due to thromboembolic events with high prevalence of recurrent venous ulcers, venous insufficiency, recurrent venous and arterial thromboembolism leading to deep venous thrombosis or pulmonary embolism. EXPERT OPINION Considering the unequivocal finding of increased mortality of KS patients, we suggest a periodic cardiovascular follow up in specialized centers with multidisciplinary care teams that comprise endocrinologists and cardiologists dedicated to KS syndrome.
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Affiliation(s)
- Giacomo Accardo
- a Department of Medical, Surgical, Neurologic , Metabolic and Aging Sciences, University of Campania "L. Vanvitelli" Naples , Naples , Italy
| | - Vanda Amoresano Paglionico
- a Department of Medical, Surgical, Neurologic , Metabolic and Aging Sciences, University of Campania "L. Vanvitelli" Naples , Naples , Italy
| | - Rosa Di Fraia
- a Department of Medical, Surgical, Neurologic , Metabolic and Aging Sciences, University of Campania "L. Vanvitelli" Naples , Naples , Italy
| | - Antonio Cittadini
- b Department of Translational Medical Sciences , Federico II University School of Medicine , Naples , Italy
| | - Andrea Salzano
- b Department of Translational Medical Sciences , Federico II University School of Medicine , Naples , Italy
| | - Daniela Esposito
- a Department of Medical, Surgical, Neurologic , Metabolic and Aging Sciences, University of Campania "L. Vanvitelli" Naples , Naples , Italy
- c Department of Endocrinology Institute of Medicine , Sahlgrenska Academy, University of Gothenburg and Sahlgrenska University Hospital , Gothenburg , Sweden
| | - Annamaria De Bellis
- a Department of Medical, Surgical, Neurologic , Metabolic and Aging Sciences, University of Campania "L. Vanvitelli" Naples , Naples , Italy
| | - Daniela Pasquali
- a Department of Medical, Surgical, Neurologic , Metabolic and Aging Sciences, University of Campania "L. Vanvitelli" Naples , Naples , Italy
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Urine miR-21-5p as a potential biomarker for predicting effectiveness of tadalafil in benign prostatic hyperplasia. Future Sci OA 2018; 4:FSO304. [PMID: 30057782 PMCID: PMC6060390 DOI: 10.4155/fsoa-2018-0012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 02/26/2018] [Indexed: 11/17/2022] Open
Abstract
Aim: To investigate whether urine levels of miRNAs that regulate the function of endothelial cells are associated with effectiveness in benign prostatic hyperplasia (BPH) patients treated with a phosphodiesterase type 5 inhibitor, tadalafil. Patients & methods: We measured urine levels of three miRNAs (miR-21-5p, miR-126-5p & miR-155-5p) in 55 BPH patients before and after tadalafil administration to understand its effectiveness. Results: Baseline urine miR-21-5p level was an independent predictor of response to tadalafil in multivariate regression analysis (odds ratio: 0.28; 95% CI: 0.10–0.77; p = 0.014). Receiver operator curve analysis revealed that baseline urine miR-21-5p could serve as a predictor of response (area under curve: 0.85; 95% CI: 0.75–0.95; p < 0.001). Conclusion: Urine miR-21-5p could serve as a biomarker in predicting response of tadalafil for BPH. Tadalafil, a phosphodiesterase type 5 inhibitor, has a high potential for treating male lower urinary tract symptoms; however, there are few reports regarding which portion of the population is appropriate for treatment with tadalafil. This study showed that the baseline urine levels of miR-21-5p, an endothelium-associated miRNA, strongly correlates with response to tadalafil and have the potential to be a predictive biomarker of whether treatment with tadalafil is suitable.
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Elmadbouh I, Ashraf M. Tadalafil, a long acting phosphodiesterase inhibitor, promotes bone marrow stem cell survival and their homing into ischemic myocardium for cardiac repair. Physiol Rep 2018; 5:5/21/e13480. [PMID: 29138357 PMCID: PMC5688776 DOI: 10.14814/phy2.13480] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Accepted: 09/23/2017] [Indexed: 12/31/2022] Open
Abstract
The aim was to evaluate the tadalafil‐mediated effects at molecular level on bone marrow‐derived mesenchymal stem cells (MSCs) survival and their homing into the infarcted hearts to promote cardiac repair and improve function. MSCs were pretreated in vitro with inhibitors of PKG, MAPK, FasL, nitric oxide synthase (NOS) (L‐NAME), CXCR4 (AMD3100), or miR‐21 inhibitors (+/−luciferase construction +/−Fas) prior to tadalafil treatment for 2 h. These MSCs were then subjected to H2O2 stress to assess their injury. Rats were subjected to acute myocardial infarction (AMI), and then followed by injection of saline or 1.5 x 106 MSCs‐treated ± tadalafil into infarcted and peri‐infarcted area. In another group, AMI was performed in 1‐month post‐myelo‐ablated rats and were injected intraperitoneally (IP) with tadalafil ± AMD3100 or L‐NAME for 5 days. Also, in another group, AMI mice were treated with IP ± tadalafil before intravenous injection with 111In‐oxine‐MSCs followed by CT/SPECT imaging to locate mobilized MSCs. Cardiac function was assessed by echocardiography. MSCs and heart extracts were analyzed by molecular bioassays. Tadalafil‐treated MSCs had higher expression of cGMP, NOS, SDF‐1α, p‐VASP, p‐Erk1/2, p‐STAT3, p‐Akt, PKG1 and Bcl‐xl; expression of these molecules was reduced with PKG1, MAPK, NOS or FasL inhibitors. Tadalafil inhibited apoptosis through increased miR‐21 expression and improved cell survival by inhibiting Fas (restored by PKG1, MAPK or miR‐21 inhibitors). In vivo, heart function, grafted cell survival, MSCs mobilization and homing were improved in tadalafil‐treated AMI animals versus controls. Conclusions: Tadalafil prolonged MSCs survival via up‐regulation of miR‐21 dependent suppression of Fas, and increased MSCs mobilization and their homing into infarcted myocardium resulting in improved cardiac repair and function.
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Affiliation(s)
- Ibrahim Elmadbouh
- Department of Emergency Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, Ohio State University, Columbus, Ohio.,Faculty of Medicine, Menoufia University, Shebin Elkom, Egypt
| | - Muhammad Ashraf
- Department of Emergency Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, Ohio State University, Columbus, Ohio
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Higashi Y. Lower urinary tract symptoms/benign prostatic hypertrophy and vascular function: Role of the nitric oxide-phosphodiesterase type 5-cyclic guanosine 3',5'-monophosphate pathway. Int J Urol 2017; 24:412-424. [PMID: 28332240 DOI: 10.1111/iju.13336] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 02/19/2017] [Indexed: 11/30/2022]
Abstract
It is well known that there is an association of lower urinary tract symptoms/benign prostatic hypertrophy with cardiovascular disease, suggesting that lower urinary tract symptoms/benign prostatic hypertrophy is a risk factor for cardiovascular events. Vascular function, including endothelial function and vascular smooth muscle function, is involved in the pathogenesis, maintenance and development of atherosclerosis, leading to cardiovascular events. Vascular dysfunction per se should also contribute to lower urinary tract symptoms/benign prostatic hypertrophy. Both lower urinary tract symptoms/benign prostatic hypertrophy and vascular dysfunction have cardiovascular risk factors, such as hypertension, dyslipidemia, diabetes mellitus, aging, obesity and smoking. Inactivation of the phosphodiesterase type 5-cyclic guanosine 3',5'-monophosphate-nitric oxide pathway causes lower urinary tract symptoms/benign prostatic hypertrophy through an enhancement of sympathetic nervous activity, endothelial dysfunction, increase in Rho-associated kinase activity and vasoconstriction, and decrease in blood flow of pelvic viscera. Both endogenous nitric oxide and exogenous nitric oxide act as vasodilators on vascular smooth muscle cells through an increase in the content of cyclic guanosine 3',5'-monophosphate, which is inactivated by phosphodiesterase type 5. In a clinical setting, phosphodiesterase type 5 inhibitors are widely used in patients with lower urinary tract symptoms/benign prostatic hypertrophy. Phosphodiesterase type 5 inhibitors might have beneficial effects on vascular function through not only inhibition of cyclic guanosine 3',5'-monophosphate degradation, but also increases in testosterone levels and nitric oxide bioavailability, increase in the number and improvement of the function of endothelial progenitor cells, and decrease in insulin resistance. In the present review, the relationships between lower urinary tract symptoms/benign prostatic hypertrophy, the phosphodiesterase type 5-nitric oxide-cyclic guanosine 3',5'-monophosphate pathway, vascular function and cardiovascular outcomes are examined.
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Affiliation(s)
- Yukihito Higashi
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University Hospital, Hiroshima, Japan.,Divivsion of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan
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12
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Altabas V, Altabas K, Kirigin L. Endothelial progenitor cells (EPCs) in ageing and age-related diseases: How currently available treatment modalities affect EPC biology, atherosclerosis, and cardiovascular outcomes. Mech Ageing Dev 2016; 159:49-62. [PMID: 26919825 DOI: 10.1016/j.mad.2016.02.009] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 01/25/2016] [Accepted: 02/22/2016] [Indexed: 12/15/2022]
Abstract
Endothelial progenitor cells (EPCs) are mononuclear cells that circulate in the blood and are derived from different tissues, expressing cell surface markers that are similar to mature endothelial cells. The discovery of EPCs has lead to new insights in vascular repair and atherosclerosis and also a new theory for ageing. EPCs from the bone marrow and some other organs aid in vascular repair by migrating to distant vessels where they differentiate into mature endothelial cells and replace old and injured endothelial cells. The ability of EPCs to repair vascular damage depends on their number and functionality. Currently marketed drugs used in a variety of diseases can modulate these characteristics. In this review, the effect of currently available treatment options for cardiovascular and metabolic disorders on EPC biology will be discussed. The various EPC-based therapies that will be discussed include lipid-lowering agents, antihypertensive agents, antidiabetic drugs, phosphodiesteraze inhibitors, hormones, as well as EPC capturing stents.
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Affiliation(s)
- Velimir Altabas
- Department of Internal Medicine, University Clinical Hospital "Sestre milosrdnice", Zagreb, Croatia.
| | - Karmela Altabas
- Department of Internal Medicine, University Clinical Hospital "Sestre milosrdnice", Zagreb, Croatia.
| | - Lora Kirigin
- Department of Internal Medicine, University Clinical Hospital "Sestre milosrdnice", Zagreb, Croatia.
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Abstract
Erectile dysfunction (ED) is a common complication of diabetes, affecting up to 75% of all diabetic men. Although the aetiology of diabetic ED is multifactorial, endothelial dysfunction is recognized as a mainstay in the pathophysiology of the disease. Endothelial dysfunction is induced by the detrimental actions of high glucose levels and increased oxidative stress on endothelial cells that make up the vascular lining. Besides directly injuring the endothelium, diabetes might also hamper vascular repair mechanisms of angiogenesis and vasculogenesis. These states exacerbate and maintain endothelial dysfunction, impairing vasorelaxation events and cavernosal blood perfusion, which are crucial for normal erectile function.
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Martínez-Salamanca JI, Zurita M, Costa C, Martínez-Salamanca E, Fernández A, Castela A, Vaquero J, Carballido J, Angulo J. Dual Strategy With Oral Phosphodiesterase Type 5 Inhibition and Intracavernosal Implantation of Mesenchymal Stem Cells Is Superior to Individual Approaches in the Recovery of Erectile and Cavernosal Functions After Cavernous Nerve Injury in Rats. J Sex Med 2016; 13:1-11. [DOI: 10.1016/j.jsxm.2015.12.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2015] [Accepted: 11/30/2015] [Indexed: 01/21/2023]
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Lanuti P, Rotta G, Almici C, Avvisati G, Budillon A, Doretto P, Malara N, Marini M, Neva A, Simeone P, Di Gennaro E, Leone A, Falda A, Tozzoli R, Gregorj C, Di Cerbo M, Trunzo V, Mollace V, Marchisio M, Miscia S. Endothelial progenitor cells, defined by the simultaneous surface expression of VEGFR2 and CD133, are not detectable in healthy peripheral and cord blood. Cytometry A 2015; 89:259-70. [DOI: 10.1002/cyto.a.22730] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Revised: 05/18/2015] [Accepted: 07/16/2015] [Indexed: 11/09/2022]
Affiliation(s)
- Paola Lanuti
- Department of Medicine and Aging Science; School of Medicine and Health Science, University “G. d'Annunzio” of Chieti-Pescara; Chieti 66013 Italy
- Center for Ageing Sciences (Ce.S.I.), “Università G. d'Annunzio” Foundation; Chieti 66013 Italy
| | | | - Camillo Almici
- Department of Transfusion Medicine; Laboratory for Stem Cells Manipulation and Cryopreservation, AO Spedali Civili di Brescia; Brescia 25123 Italy
| | - Giuseppe Avvisati
- Department of Hematology; Stem Cell Transplantation, Transfusion Medicine and Cellular Therapy, Campus Bio-Medico University Hospital; Rome 00128 Italy
| | - Alfredo Budillon
- Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS; Naples 80131 Italy
| | - Paolo Doretto
- Department of Laboratory Medicine; Clinical Pathology Laboratory, “S. Maria Degli Angeli” Hospital; Pordenone 33170 Italy
| | - Natalia Malara
- Department of Health Science; Interregional Research Center for Food Safety and Health (IRC-FSH), University “Magna Graecia” of Catanzaro; Catanzaro 88100 Italy
- Department of Experimental and Clinical Medicine; BioNEM Lab, University “Magna Graecia” of Catanzaro, Catanzaro 88100; Italy
| | - Mirella Marini
- Department of Transfusion Medicine; Laboratory for Stem Cells Manipulation and Cryopreservation, AO Spedali Civili di Brescia; Brescia 25123 Italy
| | - Arabella Neva
- Department of Transfusion Medicine; Laboratory for Stem Cells Manipulation and Cryopreservation, AO Spedali Civili di Brescia; Brescia 25123 Italy
| | - Pasquale Simeone
- Department of Medicine and Aging Science; School of Medicine and Health Science, University “G. d'Annunzio” of Chieti-Pescara; Chieti 66013 Italy
- Center for Ageing Sciences (Ce.S.I.), “Università G. d'Annunzio” Foundation; Chieti 66013 Italy
| | - Elena Di Gennaro
- Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS; Naples 80131 Italy
| | - Alessandra Leone
- Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS; Naples 80131 Italy
| | - Alessandra Falda
- Department of Laboratory Medicine; Clinical Pathology Laboratory, “S. Maria Degli Angeli” Hospital; Pordenone 33170 Italy
| | - Renato Tozzoli
- Department of Laboratory Medicine; Clinical Pathology Laboratory, “S. Maria Degli Angeli” Hospital; Pordenone 33170 Italy
| | - Chiara Gregorj
- Department of Hematology; Stem Cell Transplantation, Transfusion Medicine and Cellular Therapy, Campus Bio-Medico University Hospital; Rome 00128 Italy
| | - Melania Di Cerbo
- Department of Hematology; Stem Cell Transplantation, Transfusion Medicine and Cellular Therapy, Campus Bio-Medico University Hospital; Rome 00128 Italy
| | - Valentina Trunzo
- Department of Health Science; Interregional Research Center for Food Safety and Health (IRC-FSH), University “Magna Graecia” of Catanzaro; Catanzaro 88100 Italy
| | - Vincenzo Mollace
- Department of Health Science; Interregional Research Center for Food Safety and Health (IRC-FSH), University “Magna Graecia” of Catanzaro; Catanzaro 88100 Italy
| | - Marco Marchisio
- Department of Medicine and Aging Science; School of Medicine and Health Science, University “G. d'Annunzio” of Chieti-Pescara; Chieti 66013 Italy
- Center for Ageing Sciences (Ce.S.I.), “Università G. d'Annunzio” Foundation; Chieti 66013 Italy
| | - Sebastiano Miscia
- Department of Medicine and Aging Science; School of Medicine and Health Science, University “G. d'Annunzio” of Chieti-Pescara; Chieti 66013 Italy
- Center for Ageing Sciences (Ce.S.I.), “Università G. d'Annunzio” Foundation; Chieti 66013 Italy
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Altabas V, Altabas K. DPP-4 inhibition improves a sexual condition? Med Hypotheses 2015; 85:124-6. [PMID: 25913811 DOI: 10.1016/j.mehy.2015.04.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 04/11/2015] [Indexed: 10/23/2022]
Abstract
Erectile dysfunction (ED) is a condition of persistent inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse. The etiology of ED is predominantly vascular, explained by nitric oxide metabolism disturbances being in the background. Nitric oxide enhancing drugs like phosphodiesterase 5 inhibitors, which delay the breakdown of nitric oxide, are widely used, but still without complete success. Restauration of endogenous nitric oxide production focused on improving endothelial dysfunction could be a more effective way of treatment, addressing also other vessels in the body and preventing more serious cardiovascular disease. Endothelial progenitor cells are bone marrow-derived cells found also in human circulation, and may under circumstances be embedded into the vascular intima leading to improvements in nitric oxide production and thus in endothelial function in many organs, including the penis. In this article we hypothesize the potential role of DPP-4 inhibitors, a novel class of antidiabetic drugs in increasing the number of circulating endothelial progenitor cells. Speculated mechanisms include several substrates for DPP-4 inhibitors: GLP-1, SDF-1α, substance P, and PACAP. As DPP-4 inhibitors show favorable safety profiles and do not cause hypoglycemia, they seem to be an attractive treatment option, at least in diabetic patients, and could become a part of vascular regenerative pharmacotherapy, ameliorating also symptoms related to erectile dysfunction. Since erectile dysfunction may precede other cardiovascular vascular events, because the penile arteries are smaller in size and therefore more susceptible to decreased nitric oxide production, treating this condition with an agent affecting positively also other blood vessels could help in preventing other cardiovascular events, including myocardial infarction and stroke. However, caution is required, because DPP-4 inhibitors are a heterogenous class of drugs, with variations regarding strength and duration of action, as well as selectivity and cardiovascular safety profile, which may affect properties other than those important in glucocontrol.
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Affiliation(s)
- V Altabas
- Department of Internal Medicine, University Hospital Centre "Sestre milosrdnice", Zagreb, Croatia.
| | - K Altabas
- Department of Internal Medicine, University Hospital Centre "Sestre milosrdnice", Zagreb, Croatia
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17
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Suzuki E, Nishimatsu H, Homma Y. Stem cell therapy for erectile dysfunction. World J Clin Urol 2014; 3:272-282. [DOI: 10.5410/wjcu.v3.i3.272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Revised: 05/03/2014] [Accepted: 10/10/2014] [Indexed: 02/06/2023] Open
Abstract
Erectile dysfunction (ED) is an important health problem that has commonly been clinically treated using phosphodiesterase type 5 inhibitors (PDE5Is). However, PDE5Is are less effective when the structure of the cavernous body has been severely injured, and thus regeneration is required. Stem cell therapy has been investigated as a possible means for regenerating the injured cavernous body. Stem cells are classified into embryonic stem cells and adult stem cells (ASCs), and the intracavernous injection of ASCs has been explored as a therapy in animal ED models. Bone marrow-derived mesenchymal stem cells and adipose tissue-derived stem cells are major sources of ASCs used for the treatment of ED, and accumulated evidence now suggests that ASCs are useful in the restoration of erectile function and the regeneration of the cavernous body. However, the mechanisms by which ASCs recover erectile function remain controversial. Some studies indicated that ASCs were differentiated into the vascular endothelial cells, vascular smooth muscle cells, and nerve cells that originally resided in the cavernous body, whereas other studies have suggested that ASCs improved erectile function via the secretion of anti-apoptotic and/or proangiogenic cytokines rather than differentiation into other cell types. In this paper, we reviewed the characteristics of stem cells used for the treatment of ED, and the possible mechanisms by which these cells exert their effects. We also discussed the problems to be solved before implementation in the clinical setting.
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Pelliccione F, D'Angeli A, D'Andrea S, Barbonetti A, Pezzella A, Necozione S, Falone S, Amicarelli F, Francavilla F, Francavilla S. Tadalafil treatment had a modest effect on endothelial cell damage and repair ability markers in men with erectile dysfunction and vascular risk. Asian J Androl 2014; 16:290-4. [PMID: 24407182 PMCID: PMC3955343 DOI: 10.4103/1008-682x.122347] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
The number of the circulating angiogenic cells (CACs) and colony forming units (CFUs) derived from cultured circulating mononuclear cells (MNCs) represents a laboratory surrogate for endothelial cell repair ability. The serum of men with erectile dysfunction (ED) and vascular risk factors (VRFs) showed an increased level of endothelial cell damage/dysfunction markers and reduced the numbers of CACs and CFUs derived from the cells of healthy men. We analyzed whether treating men with ED and VRFs with the selective phosphodiesterase type 5 inhibitor tadalafil improved the endothelial cell repair ability and reduced the levels of the serum markers of endothelial cell damage/dysfunction. MNCs from healthy men were cultured with 20% serum from 36 ED patients to obtain CACs and CFUs. The ED patients were evaluated before and after 4 weeks of treatment with tadalafil (20 mg every other day) or with a placebo. The tadalafil treatment improved erectile function (P = 0.0028), but had no effect on the inhibitory effects of serum from ED patients on the CACs and CFUs derived from healthy men. The levels of endothelin-1 (P = 0.011) and tissue type plasminogen activator (P = 0.005) were reduced after treatment compared to baseline and those of the placebo group, whereas no changes were observed in the E-selectin levels. The tadalafil treatment in the ED patients with VRFs resulted in only a modest effect on the laboratory measures of the endothelial cell damage/dysfunction and repair ability. The proposed beneficial effect of phosphodiesterase type 5 inhibition on vascular homeostasis requires further analysis.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Sandro Francavilla
- Department of Life, Health and Environmental Sciences, Section of Andrology, University of L'Aquila, L'Aquila, Italy
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Abstract
Stem cell (SC) therapy for erectile dysfunction (ED) has been investigated in 35 published studies, with one being a small-scale clinical trial. Out of these 35 studies, 19 are concerned with cavernous nerve (CN) injury-associated ED while 10 with diabetes mellitus- (DM-) associated ED. Adipose-derived SCs (ADSCs) were employed in 18 studies while bone marrow SCs (BMSCs) in 9. Transplantation of SCs was done mostly by intracavernous (IC) injection, as seen in 25 studies. Allogeneic and xenogeneic transplantations have increasingly been performed but their immune-incompatibility issues were rarely discussed. More recent studies also tend to use combinatory therapies by modifying or supplementing SCs with angiogenic or neurotrophic genes or proteins. All studies reported better erectile function with SC transplantation, and the majority also reported improved muscle, endothelium, and/or nerve in the erectile tissue. However, differentiation or engraftment of transplanted SCs has rarely been observed; thus, paracrine action is generally believed to be responsible for SC’s therapeutic effects. But still, few studies actually investigated and none proved paracrine action as a therapeutic mechanism. Thus, based exclusively on functional outcome data shown in preclinical studies, two clinical trials are currently recruiting patients for treatment with IC injection of ADSC and BMSC, respectively.
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20
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Foresta C, De Toni L, Ferlin A, Di Mambro A. Clinical implication of endothelial progenitor cells. Expert Rev Mol Diagn 2014; 10:89-105. [DOI: 10.1586/erm.09.80] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Smith WB, McCaslin IR, Gokce A, Mandava SH, Trost L, Hellstrom WJ. PDE5 inhibitors: considerations for preference and long-term adherence. Int J Clin Pract 2013; 67:768-80. [PMID: 23869678 DOI: 10.1111/ijcp.12074] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION Erectile dysfunction (ED) is a highly prevalent condition affecting nearly one in five men worldwide. The advent of phosphodiesterase type 5 inhibitors (PDE5i) has revolutionised the ED treatment landscape and provided effective, minimally invasive therapies to restore male sexual function. MATERIALS AND METHODS A pubmed search was performed of all English language articles from 1996 to present reviewing PDE5i, including pharmacokinetics, efficacy profiles and comparisons, where available. RESULTS Currently available PDE5i in the United States include sildenafil, vardenafil, tadalafil and avanafil, each of which has unique side effect, pharmacokinetic and outcome profiles. Sildenafil is associated with increased rate of visual changes, vardenafil with QT prolongation and tadalafil with lower back pain. Avanafil and vardenafil orodispersible tablet rapidly achieve peak plasma concentration, which results in faster onset of action, whereas tadalafil exhibits the longest half-life. First time response to PDE5i is approximately 60-70%, with no significant differences in efficacy noted among therapies. The literature does not clearly demonstrate a preference for one drug. High-treatment success rates (89%) were reported when patients were prescribed all available PDE5i. Daily dosing with tadalafil is associated with improved erectile function (EF) over time. Finally, novel modes of patient-provider interaction, including internet-based education, communication and prescribing, may also improve long-term adherence. CONCLUSIONS PDE5i represent first line therapy for ED with excellent overall efficacy and satisfactory side effect profiles. Enhanced communciation, coupled with increased knowledge of drug characteristics, comparative treatment regimens and optimal prescribing patterns, offer compelling tools to improve long-term treatment success.
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Affiliation(s)
- W B Smith
- Department of Urology, School of Medicine, Tulane University, New Orleans, LA, USA
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Condorelli RA, Calogero AE, Vicari E, Duca Y, Favilla V, Morgia G, Cimino S, La Vignera S. Endothelial progenitor cells and erectile dysfunction: a brief review on diagnostic significance and summary of our experience. Aging Male 2013; 16:29-32. [PMID: 23597264 DOI: 10.3109/13685538.2013.789159] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The article provides a brief review of the literature concerning the diagnostic use of endothelial progenitor cells in patients with erectile dysfunction. In particular, patients with arterial erectile dysfunction could benefit from the use of this diagnostic marker, which in clinical practice can be used together with more conventional methods such as the penile Doppler. It is very important to acquire diagnostic tools for the diagnosis of sub clinical form of endothelial dysfunction in these patients, in particular when the erectile dysfunction is associated with cardiovascular risk factors.
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Affiliation(s)
- Rosita A Condorelli
- Department of Medical and Pediatric Sciences, University of Catania, Catania, Italy
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Condorelli RA, Calogero AE, Vicari E, Favilla V, Morgia G, Cimino S, La Vignera S. Vascular regenerative therapies for the treatment of erectile dysfunction: current approaches. Andrology 2013; 1:533-40. [DOI: 10.1111/j.2047-2927.2013.00087.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2013] [Revised: 03/01/2013] [Accepted: 03/09/2013] [Indexed: 12/20/2022]
Affiliation(s)
- R. A. Condorelli
- Section of Endocrinology; Andrology and Internal Medicine; Department of Medical and Pediatric Sciences; University of Catania; Catania; Italy
| | - A. E. Calogero
- Section of Endocrinology; Andrology and Internal Medicine; Department of Medical and Pediatric Sciences; University of Catania; Catania; Italy
| | - E. Vicari
- Section of Endocrinology; Andrology and Internal Medicine; Department of Medical and Pediatric Sciences; University of Catania; Catania; Italy
| | - V. Favilla
- Department of Urology; University of Catania; Catania; Italy
| | - G. Morgia
- Department of Urology; University of Catania; Catania; Italy
| | - S. Cimino
- Department of Urology; University of Catania; Catania; Italy
| | - S. La Vignera
- Section of Endocrinology; Andrology and Internal Medicine; Department of Medical and Pediatric Sciences; University of Catania; Catania; Italy
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Schwartz BG, Jackson G, Stecher VJ, Campoli-Richards DM, Kloner RA. Phosphodiesterase type 5 inhibitors improve endothelial function and may benefit cardiovascular conditions. Am J Med 2013; 126:192-9. [PMID: 23410557 DOI: 10.1016/j.amjmed.2012.08.015] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Revised: 08/29/2012] [Accepted: 08/29/2012] [Indexed: 11/19/2022]
Abstract
The effects of phosphodiesterase type 5 inhibitors on vasodilation mediated via nitric oxide-cyclic guanosine monophosphate are well described. Less is known about other mechanisms through which phosphodiesterase type 5 inhibitors benefit endothelial function, including normalization of serum biomarkers, increased levels of endothelial progenitor cells, ischemia-reperfusion protection mechanisms, and other actions specific to patients with diabetes. These various mechanisms are reviewed. Their impact on several cardiovascular diseases, including erectile dysfunction, pulmonary hypertension, heart failure, high-altitude pulmonary edema, Raynaud's phenomenon, coronary artery disease, diabetes, and atherosclerosis, is presented.
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Affiliation(s)
- Bryan G Schwartz
- Heart Institute, Good Samaritan Hospital, Los Angeles, Calif 90017-2395, USA
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25
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Porst H, Hell-Momeni K, Büttner H. Chronic PDE-5 inhibition in patients with erectile dysfunction – a treatment approach using tadalafil once-daily. Expert Opin Pharmacother 2012; 13:1481-94. [DOI: 10.1517/14656566.2012.693162] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Qiu XF, Li XX, Chen Y, Lin HC, Yu W, Wang R, Dai YT. Mobilisation of endothelial progenitor cells: one of the possible mechanisms involved in the chronic administration of melatonin preventing erectile dysfunction in diabetic rats. Asian J Androl 2012; 14:481-6. [PMID: 22367180 DOI: 10.1038/aja.2011.161] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Diabetes-induced oxidative stress plays a critical role in the mobilisation of endothelial progenitor cells (EPCs) from the bone marrow to the circulation. This study was designed to explore the effects of chronic melatonin administration on the promotion of the mobilisation of EPCs and on the preservation of erectile function in type I diabetic rats. Melatonin was administered to streptozotocin-induced type I diabetic rats. EPCs levels were determined using flow cytometry. Oxidative stress in the bone marrow was indicated by the levels of superoxide dismutase and malondialdehyde. Erectile function was evaluated by measuring the intracavernous pressure during an electrostimulation of the cavernous nerve. The density of the endothelium and the proportions of smooth muscle and collagen in the corpus cavernosum were determined by immunohistochemistry. The administration of melatonin increased the superoxide dismutase level and decreased the malondialdehyde level in the bone marrow. This effect was accompanied by an increased level of circulating EPCs in the diabetic rats. The intracavernous pressure to mean arterial pressure ratio of the rats in the treatment group was significantly greater, compared with diabetic control rats. The histological analysis demonstrated an increase in the endothelial density of the corpus cavernosum after the administration of melatonin. However, melatonin treatment did not change the proportions of smooth muscle and collagen in the corpus cavernosum of diabetic rats. Chronic administration of melatonin has a beneficial effect on preventing erectile dysfunction (ED) in type I diabetic rats. Promoting the mobilisation of EPCs is one of the possible mechanisms involved in the improvement of ED.
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Affiliation(s)
- Xue-Feng Qiu
- Department of Urology, Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
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27
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Cellular biomarkers of endothelial health: microparticles, endothelial progenitor cells, and circulating endothelial cells. ACTA ACUST UNITED AC 2012; 6:85-99. [PMID: 22321962 DOI: 10.1016/j.jash.2011.11.003] [Citation(s) in RCA: 143] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2011] [Revised: 11/17/2011] [Accepted: 11/22/2011] [Indexed: 12/13/2022]
Abstract
Endothelial dysfunction, the shift from a healthy endothelium to a damaged pro-coagulative, pro-inflammatory, and pro-vasoconstrictive phenotype, is an early event in many chronic diseases that frequently precedes cardiovascular complications. Functional assessment of the endothelium can identify endothelial damage and predict cardiovascular risk; however, this assessment provides little information as to the mechanisms underlying development of endothelial dysfunction. Changes in plasma asymmetric dimethyl arginine levels, markers of lipid peroxidation, circulating levels of inflammatory mediators, indices of coagulation and cellular surrogates such as microparticles, circulating endothelial cells, and endothelial progenitor cells may reflect alterations in endothelial status and as such have been defined as "biomarkers" of endothelial function. Biomarkers may be chemical or cellular. This review examines some markers of endothelial dysfunction, with a particular focus on cellular biomarkers of endothelial dysfunction and their diagnostic potential.
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28
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Zhang H, Albersen M, Jin X, Lin G. Stem cells: novel players in the treatment of erectile dysfunction. Asian J Androl 2012; 14:145-55. [PMID: 22002437 PMCID: PMC3735142 DOI: 10.1038/aja.2011.79] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2011] [Revised: 06/30/2011] [Accepted: 07/19/2011] [Indexed: 01/09/2023] Open
Abstract
Stem cells are defined by their capacity for both self-renewal and directed differentiation; thus, they represent great promise for regenerative medicine. Historically, stem cells have been categorized as either embryonic stem cells (ESCs) or adult stem cells (ASCs). It was previously believed that only ESCs hold the ability to differentiate into any cell type, whereas ASCs have the capacity to give rise only to cells of a given germ layer. More recently, however, numerous studies demonstrated the ability of ASCs to differentiate into cell types beyond their tissue origin. The aim of this review was to summarize contemporary evidence regarding stem cell availability, differentiation, and more specifically, the potential of these cells in the diagnosis and treatment of erectile dysfunction (ED) in both animal models and human research. We performed a search on PubMed for articles related to definition, localisation and circulation of stem cells as well as the application of stem cells in both diagnosis and treatment of ED. Strong evidence supports the concept that stem cell therapy is potentially the next therapeutic approach for ED. To date, a large spectrum of stem cells, including bone marrow mesenchymal stem cells, adipose tissue-derived stem cells and muscle-derived stem cells, have been investigated for neural, vascular, endothelial or smooth muscle regeneration in animal models for ED. In addition, several subtypes of ASCs are localized in the penis, and circulating endogenous stem cells can be employed to predict the outcome of ED and ED-related cardiovascular diseases.
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Affiliation(s)
- Haiyang Zhang
- Minimally Invasive Urology Center, Provincial Hospital Affiliated to Shandong University, Jinan, China
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29
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Mazzola C, Mulhall JP. Penile rehabilitation after prostate cancer treatment: outcomes and practical algorithm. Urol Clin North Am 2011; 38:105-18. [PMID: 21621077 DOI: 10.1016/j.ucl.2011.03.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The number of patients diagnosed with prostate cancer was estimated to be 192,000 in 2009 according to the American Cancer Society. The prevalence of reported erectile dysfunction after radical prostatectomy has significant variance. Among the studies in which the nerve-sparing status was described, erectile function recovery adequate for sexual intercourse was achieved in 50% of patients. This article reviews the animal and human studies in this field and provides a useful penile rehabilitation algorithm.
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Affiliation(s)
- Clarisse Mazzola
- Male Sexual & Reproductive Medicine Program, Division of Urology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
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30
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Effects of phosphodiesterase type 5 inhibitors on endothelial function and cardiovascular autonomic nerve function in men. JOURNAL OF MENS HEALTH 2011. [DOI: 10.1016/j.jomh.2011.01.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Fusco F, Razzoli E, Imbimbo C, Rossi A, Verze P, Mirone V. A new era in the treatment of erectile dysfunction: chronic phosphodiesterase type 5 inhibition. BJU Int 2010; 105:1634-9. [PMID: 20553468 DOI: 10.1111/j.1464-410x.2010.09244.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Historically, oral phosphodiesterase type 5 inhibitors (PDE5-i) have been prescribed with an 'as-necessary' regimen for treating erectile dysfunction (ED), thus addressing primarily symptom relief. However, approximately 30% of patients are unresponsive to on-demand PDE5-i regimens due to both psychogenic and organic factors and, although it is difficult to estimate the proportion, discontinuation rates remain high. In recent years, a 2.5-5 mg daily dose of tadalafil has been proposed and was recently approved for treating ED. Chronic PDE-5 inhibition has the advantage of potentially 'curing' ED, on a daily basis, by interfering with pathophysiological factors of both psychogenic (anxiety related to planning sexual activity) and organic (endothelial dysfunction, penile structural homeostasis) origin, although further research is needed to better address these hypotheses. Clinical studies showed that chronic PDE5-i regimens are a safe and effective alternative to the classical on-demand dosage, and might improve the outcomes in a selected group of patients.
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Affiliation(s)
- Ferdinando Fusco
- Department of Urology, University Federico II of Naples, Naples, Italy
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Foresta C, De Toni L, Selice R, Garolla A, Di Mambro A. Increased osteocalcin-positive endothelial progenitor cells in hypogonadal male patients. J Endocrinol Invest 2010; 33:439-42. [PMID: 20671406 DOI: 10.1007/bf03346620] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Endothelial dysfunction is considered a key factor in the development of cardiovascular diseases. Endothelial regeneration is necessary for the maintenance of endothelial function and circulating endothelial progenitor cells (EPC) participate of it in both direct and indirect manner. The molecular phenotype of EPC is not univocally defined and recent studies identified an osteocalcin (OCN)-positive (EPC-OCN+) subpopulation of EPC highly correlated with atherosclerosis progression. AIM Considering that hypogonadism is a risk factor for cardiovascular diseases and atherosclerosis, we investigated the circulating levels of EPC-OCN+ in hypogonadal patients. SUBJECTS AND METHODS Ten hypogonadotropic hypogonadal (HH) male patients and 30 healthy eugonadal men were evaluated for clinical status and hormonal levels. Circulating levels of CD34+/CD133+/kinase insert domain-receptor+ EPC and EPC-OCN+ were also determined by flow cytometry. RESULTS Compared to controls, HH patients displayed lower FSH, LH, estradiol, testosterone, and EPC levels. On the contrary, EPC-OCN+ were significantly increased. CONCLUSIONS The observed association of low levels of circulating EPC and increased values of EPC-OCN+ sub-population in hypogonadal men strengthens the significance of hypogonadism as cardiovascular risk factor.
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Affiliation(s)
- C Foresta
- Department of Histology, Microbiology and Medical Biotechnologies, Section of Clinical Pathology and Centre for Male Gamete Cryopreservation, University of Padua, Via Gabelli 63, 35121 Padua, Italy.
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Everaert BR, Van Craenenbroeck EM, Hoymans VY, Haine SE, Van Nassauw L, Conraads VM, Timmermans JP, Vrints CJ. Current perspective of pathophysiological and interventional effects on endothelial progenitor cell biology: focus on PI3K/AKT/eNOS pathway. Int J Cardiol 2010; 144:350-66. [PMID: 20444511 DOI: 10.1016/j.ijcard.2010.04.018] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2010] [Accepted: 04/04/2010] [Indexed: 12/24/2022]
Abstract
For more than a decade, endothelial progenitor cells (EPCs) have been implicated in cardiovascular homeostasis. EPCs are believed to reside within the bone marrow in close contact with surrounding stromal cells, and, under stimulation of pro-inflammatory cytokines, EPCs are mobilized out of the bone marrow. Hereafter circulating EPCs home to peripheral tissues, undergoing further proliferation and differentiation. Under certain pathophysiologic conditions this process seems to be blunted, resulting in a reduced capacity of EPCs to engage in vasculogenesis at sites of endothelial injury or tissue ischemia. In this review, we focus on the effects of traditional cardiovascular risk factors on EPC biology and we explore whether pharmacological, dietary and lifestyle interventions can favorably restore EPC mobilization, differentiation, homing and angiogenic properties. Because the PI3K/Akt/eNOS pathway plays a pivotal role in the process of EPC mobilization, migration and homing, we specifically emphasize the involvement of PI3K, Akt and eNOS in EPC biology under these different (patho)physiologic conditions. (Pre)clinically used drugs or lifestyle interventions that have been shown to ameliorate EPC biology are reviewed. These treatment strategies remain attractive targets to restore the regenerative capacity of EPCs in cardiovascular diseases.
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Affiliation(s)
- Bert R Everaert
- Laboratory of Cell Biology and Histology, University of Antwerp, Antwerp, Belgium
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Mulhall JP, Bella AJ, Briganti A, McCullough A, Brock G. Erectile Function Rehabilitation in the Radical Prostatectomy Patient. J Sex Med 2010; 7:1687-98. [PMID: 20388165 DOI: 10.1111/j.1743-6109.2010.01804.x] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- John P Mulhall
- Memorial Sloan-Kettering Cancer Center, Sexual and Reproductive Medicine, New York, NY, USA
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Aversa A. Systemic and metabolic effects of PDE5-inhibitor drugs. World J Diabetes 2010; 1:3-7. [PMID: 21537421 PMCID: PMC3083877 DOI: 10.4239/wjd.v1.i1.3] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2009] [Revised: 11/30/2009] [Accepted: 12/07/2009] [Indexed: 02/05/2023] Open
Abstract
Phosphodiesterase type-5 inhibitor (PDE5-i) drugs were first marketed in 1998 (sildenafil) for 'ondemand' treatment of male erectile dysfunction (ED) of any origin. They selectively inhibit intrapenile PDE5 isoenzyme which in turn increases intracellular cyclic guanosine monophosphate levels, thus resulting in prolonged relaxation of cavernosum smooth muscle cells and facilitating the erectile process. Since 2003, two new molecules (tadalafil and vardenafil) have been introduced, resulting in greater interest in these compounds and leading patients to ask for more prescriptions from their doctors. The vast use of PDE5-i in diabetic and cardiovascular ED patients led researchers to investigate their possible extra sexual effects. Several studies investigating their effects on endothelium, coronary and pulmonary circulation, inferior oesophageal sphincter and kidney functions have appeared and, finally, sildenafil was approved for the treatment of pulmonary arterial hypertension. Recent animal studies highlighted a possible interaction between chronic PDE5 inhibition and glucose homeostasis which occurs through a marked improvement of high fat diet induced insulin resistance. If this data is extended to humans, a new scenario will be opened for the chronic use of PDE5-i for sexual rehabilitation along with cardiovascular and metabolic benefits.
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Affiliation(s)
- Antonio Aversa
- Antonio Aversa, Department of Medical Pathophysiology, Sapienza University of Rome, Viale del Policlinico 155, Rome 00161, Italy
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Di Mambro A, Ferlin A, De Toni L, Selice R, Caretta N, Foresta C. Endothelial progenitor cells as a new cardiovascular risk factor in Klinefelter's syndrome. Mol Hum Reprod 2010; 16:411-7. [DOI: 10.1093/molehr/gaq015] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Garolla A, D'Incà R, Checchin D, Biagioli A, De Toni L, Nicoletti V, Scarpa M, Bolzonello E, Sturniolo GC, Foresta C. Reduced endothelial progenitor cell number and function in inflammatory bowel disease: a possible link to the pathogenesis. Am J Gastroenterol 2009; 104:2500-7. [PMID: 19568231 DOI: 10.1038/ajg.2009.332] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Circulating endothelial progenitor cells (EPCs) are essential for endothelial repair and vascular healing. Patients with inflammatory bowel disease (IBD) may suffer from endothelial dysfunction. Reduced EPC number, impaired mobilization, or increased EPC apoptosis may be crucial in this phenomenon. The aim of our study was to investigate the number and function of EPCs in patients with IBD and to assess their endothelial function. METHODS In 100 IBD patients (47 ulcerative colitis (UC) and 53 Crohn's disease (CD)) and 50 healthy controls, EPC number, CXC motif receptor 4 (CXCR4) expression, the percentage of apoptotic circulating EPCs, and the number of colony-forming units were evaluated. Endothelial dysfunction was assessed by luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone levels, and in a subgroup of patients, brachial artery flow-mediated dilation (FMD) was measured. Kruskal-Wallis ANOVA (analysis of variance), Mann-Whitney U two-tailed, and Spearman's rank correlation tests were used to assess differences. RESULTS EPC number was significantly lower in UC patients (39.6 (95% confidence interval (95% CI): 30.7-48.6)) and in CD patients (43.1 (95% CI: 35.9-50.4)) than in healthy controls (97.1 (95% CI: 88.3-105.9)), (P<0.001). LH and FSH levels and CXCR4 expression on EPCs did not significantly differ from controls. Testosterone concentrations and FMD were lower in UC patients. Number of apoptotic EPCs was higher in both UC and CD patients with an impaired ability to generate colony in vitro. CONCLUSIONS We hypothesize that in IBD patients, apoptosis contributes to the reduction of circulating EPC number and to their ability to proliferate in vitro. As this condition represents a risk factor for cardiovascular disease, endothelial function should be evaluated in these patients.
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Affiliation(s)
- Andrea Garolla
- Department of Histology, Microbiology, and Medical Biotechnologies, Center for Male Gamete Cryopreservation, University of Padova, Padova, Italy
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Porst H, Hell-Momeni K, Büttner H. Chronische PDE-5-Hemmung bei erektiler Dysfunktion. Urologe A 2009; 48:1318, 1320-9. [DOI: 10.1007/s00120-009-2089-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Foresta C, Di Mambro A, Caretta N, De Toni L, Zuccarello D, Ferlin A. Effect of vardenafil on endothelial progenitor cells in hypogonadotrophic hypogonadal patients: role of testosterone treatment. Clin Endocrinol (Oxf) 2009; 71:412-6. [PMID: 19094070 DOI: 10.1111/j.1365-2265.2008.03507.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
CONTEXT Endothelial progenitor cells (EPCs) are bone marrow-derived cells required for endothelial repair. Circulating EPC concentration is low in conditions characterized by endothelial dysfunction but their number can be increased by treatment with phosphodiesterase-5 (PDE5) inhibitors. EPCs are also reduced in hypogonadal men and testosterone (T) treatment restores their concentration. OBJECTIVE To evaluate the relationship between the effect of PDE5 inhibitors and T on EPCs, we analysed the acute effect of vardenafil on the number of EPCs in hypogonadotrophic hypogonadal (HH) patients, before and after T treatment. DESIGN AND SETTING A case-control study at a university andrology centre. PATIENTS Fifteen HH subjects and 25 aged-matched controls. MAIN OUTCOME MEASURES The number of circulating EPCs and progenitor cells (PCs) in HH patients was evaluated after acute vardenafil administration at baseline and after 6 months of T supplementation. RESULTS At baseline, HH men had significantly lower numbers of PCs and EPCs with respect to controls and vardenafil administration had no effect on the number of these cells. After 6 months of T treatment, all HH patients were eugonadal. With respect to baseline, PCs and EPCs were significantly higher and reached the levels observed in controls. Vardenafil administration in HH men at the end of T treatment induced a significant increase in PCs and EPCs in a manner similar to that in controls. CONCLUSIONS This study showed that normal T levels are necessary to restore the responsiveness of EPCs to PDE5 inhibitors, suggesting that T positively modulates PDE5 in bone marrow.
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Affiliation(s)
- Carlo Foresta
- Department of Histology, Microbiology and Medical Biotechnologies, Section of Clinical Pathology and Centre for Male Gamete Cryopreservation, University of Padova, Padova, Italy.
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Briganti A, Capitanio U, Chun FKH, Karakiewicz PI, Salonia A, Bianchi M, Cestari A, Guazzoni G, Rigatti P, Montorsi F. Prediction of sexual function after radical prostatectomy. Cancer 2009; 115:3150-9. [DOI: 10.1002/cncr.24349] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Affiliation(s)
- Michele Ramien
- From the Division of Dermatology, University of Toronto, Toronto, ON, and the Division of Dermatology and Cutaneous Sciences, Department of Medicine, University of Alberta, Edmonton, AB
| | - Alain Brassard
- From the Division of Dermatology, University of Toronto, Toronto, ON, and the Division of Dermatology and Cutaneous Sciences, Department of Medicine, University of Alberta, Edmonton, AB
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Vlachopoulos C, Ioakeimidis N, Rokkas K, Stefanadis C. Cardiovascular Effects of Phosphodiesterase Type 5 Inhibitors. J Sex Med 2009; 6:658-74. [DOI: 10.1111/j.1743-6109.2008.01107.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Foresta C, Toni LD, Mambro AD, Garolla A, Ferlin A, Zuccarello D. ORIGINAL RESEARCH—BASIC SCIENCE: The PDE5 Inhibitor Sildenafil Increases Circulating Endothelial Progenitor Cells and CXCR4 Expression. J Sex Med 2009; 6:369-72. [DOI: 10.1111/j.1743-6109.2008.01014.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Stirban A, Laude D, Elghozi JL, Sander D, Agelink MW, Hilz MJ, Ziegler D. Acute effects of sildenafil on flow mediated dilatation and cardiovascular autonomic nerve function in type 2 diabetic patients. Diabetes Metab Res Rev 2009; 25:136-43. [PMID: 19116943 DOI: 10.1002/dmrr.921] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Sildenafil, frequently used as on demand medication for the treatment of erectile dysfunction (ED), has been suggested to improve endothelial function but also to alter blood pressure (BP) and induce sympathetic activation. In people with type 2 diabetes mellitus (T2DM), a high-risk population, the safety profile and the effects on endothelial function of a maximal sildenafil dose (100 mg) have not been investigated and therefore constituted the aim of our study. METHODS A double-blind, placebo-controlled, cross-over trial using a single dose of 100 mg sildenafil or placebo has been conducted in 40 subjects with T2DM without known CVD. Haemodynamic parameters, flow mediated dilatation (FMD) in brachial artery, cardiovascular autonomic function tests and spontaneous baroreflex sensitivity (BRS) were measured. RESULTS Sixty minutes after administration of sildenafil but not placebo, a fall of supine systolic blood pressure (SBP) (-5.41 +/- 1.87 vs. + 0.54 +/- 1.71 mmHg) and diastolic blood pressure (DBP) (-4.46 +/- 1.13 vs. + 0.89 +/- 0.94 mmHg), as well as orthostatic SBP (-7.41 +/- 2.35 vs. + 0.94 +/- 2.06 mmHg) and DBP (-5.65 +/- 1.45 vs. + 1.76 +/- 1.00 mmHg) during standing occurred, accompanied by an increase in heart rate (+1.98 +/- 0.69 vs. - 2.42 +/- 0.59 beats/min) (all p < 0.01 vs. placebo). Changes in BP to standing up, FMD, time domain and frequency domain indices of heart rate variability (HRV) and BRS were comparable between sildenafil and placebo. CONCLUSIONS Sildenafil administered at a maximum single dose to T2DM men results in a mild increase in heart rate and decrease in BP, but it induces neither an acute improvement of FMD nor any adverse effects on orthostatic BP regulation, HRV and BRS.
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Affiliation(s)
- Alin Stirban
- Diabetes Clinic, Heart and Diabetes Center North Rhine-Westphalia, Ruhr-University of Bochum, Germany.
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Giannarini G, Pomara G, Moro U, Mogorovich A, Fabris FM, Morelli G, Scott CA, Selli C. Isolated polyarteritis nodosa of the genitourinary tract presenting with severe erectile dysfunction: a case report with long-term follow-up. J Sex Med 2009; 6:1189-1193. [PMID: 19175862 DOI: 10.1111/j.1743-6109.2008.01028.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Polyarteritis nodosa (PAN) is a rare necrotizing vasculitis affecting small- and medium-sized arteries of multiple organs. Spreading to the genitourinary tract is very common, with invariable involvement of kidneys or testes, but its impact on erectile function remains undetermined. AIM We describe a case of isolated PAN of the genitourinary tract diagnosed in a young man presenting with severe erectile dysfunction (ED), debate the critical issues of the differential diagnosis, and provide the long-term follow-up outcome. METHODS The case report profiled a 36-year-old man who presented with progressively worsening erectile function and was incidentally found to suffer from genitourinary PAN. Extensive clinical, laboratory, and instrumental investigations, including brachial artery dilation test, suggested an arteriogenic etiology for ED and excluded a systemic involvement by PAN. Management featured use of a long-term, on-demand phosphodiesterase type 5 (PDE5) inhibitor regimen for ED, and close surveillance with no immunosuppressive therapy for PAN. MAIN OUTCOME MEASURES Clinical history data, brachial artery dilation test, response to PDE5 inhibitor therapy. RESULTS After 12 months of PDE5 inhibitor therapy, the patient recovered a normal erectile function, paralleled by restored endothelial function as assessed with brachial artery dilation test. At a 5-year clinical follow-up, he continued to have full erectile ability with only occasional use of PDE5 inhibitor, and no evidence of progressive PAN was documented. CONCLUSIONS We propose PAN as a novel cause of arteriogenic ED, report the effective therapy with PDE5 inhibitor, and confirm the good long-term prognosis of isolated genitourinary PAN without immunosuppressive treatment.
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Affiliation(s)
| | | | - Umberto Moro
- Division of Urology, A.S.S. "Isontina", Gorizia, Italy
| | | | | | | | | | - Cesare Selli
- Department of Urology, University of Pisa, Pisa, Italy
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Groeneweg G, Huygen FJPM, Niehof SP, Wesseldijk F, Bussmann JBJ, Schasfoort FC, Stronks DL, Zijlstra FJ. Effect of tadalafil on blood flow, pain, and function in chronic cold complex regional pain syndrome: a randomized controlled trial. BMC Musculoskelet Disord 2008; 9:143. [PMID: 18937830 PMCID: PMC2575214 DOI: 10.1186/1471-2474-9-143] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2008] [Accepted: 10/20/2008] [Indexed: 12/30/2022] Open
Abstract
Background This double-blind, randomized, controlled trial investigated the effect of the phosphodiesterase-5 inhibitor tadalafil on the microcirculation in patients with cold Complex Regional Pain Syndrome (CRPS) in one lower extremity. Methods Twenty-four patients received 20 mg tadalafil or placebo daily for 12 weeks. The patients also participated in a physical therapy program. The primary outcome measure was temperature difference between the CRPS side and the contralateral side, determined by measuring the skin temperature with videothermography. Secondary outcomes were: pain measured on a Visual Analogue Scale, muscle force measured with a MicroFet 2 dynamometer, and level of activity measured with an Activity Monitor (AM) and walking tests. Results At the end of the study period, the temperature asymmetry was not significantly reduced in the tadalafil group compared with the placebo group, but there was a significant and clinically relevant reduction of pain in the tadalafil group. Muscle force improved in both treatment groups and the AM revealed small, non-significant improvements in time spent standing, walking, and the number of short walking periods. Conclusion Tadalafil may be a promising new treatment for patients that have chronic cold CRPS due to endothelial dysfunction, and deserves further investigation. Trial Registration The registration number in the Dutch Trial Register is ISRCTN60226869.
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Affiliation(s)
- George Groeneweg
- Department of Anesthesiology, subdivision Pain Treatment Centre, Erasmus MC, Rotterdam, the Netherlands.
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Diller GP, van Eijl S, Okonko DO, Howard LS, Ali O, Thum T, Wort SJ, Bédard E, Gibbs JSR, Bauersachs J, Hobbs AJ, Wilkins MR, Gatzoulis MA, Wharton J. Circulating endothelial progenitor cells in patients with Eisenmenger syndrome and idiopathic pulmonary arterial hypertension. Circulation 2008; 117:3020-30. [PMID: 18519847 DOI: 10.1161/circulationaha.108.769646] [Citation(s) in RCA: 155] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
BACKGROUND Impaired endothelial homeostasis underlies the pathophysiology of pulmonary arterial hypertension (PAH). We speculated that PAH patients are deficient in circulating endothelial progenitor cells (EPCs), potentially contributing to endothelial dysfunction and disease progression. METHODS AND RESULTS We recruited 41 patients with Eisenmenger syndrome (13 with Down syndrome), 55 with idiopathic PAH, and 47 healthy control subjects. Flow cytometry and in vitro assays were used to quantify EPCs and to assess cell function. The number of circulating CD34+, CD34+/AC133+, CD34+/KDR+, and CD34+/AC133+/KDR+ progenitor cells was low in Eisenmenger patients compared with healthy control subjects, and those with Down syndrome displayed even fewer EPCs. Reductions in EPC numbers correlated with New York Heart Association functional class, 6-minute walk distance, and plasma brain-type natriuretic peptide levels. The capacity of cultured peripheral blood mononuclear cells to form colonies and incorporate into tube-like structures was impaired in Eisenmenger patients. Idiopathic PAH patients had reduced numbers of EPCs, and the number of circulating EPCs correlated with invasive hemodynamic parameters in this cohort. Levels of immune inflammatory markers, cGMP, stable nitric oxide oxidation products, and asymmetric dimethylarginine were abnormal in patients with PAH and related to numbers of EPCs. Within the idiopathic PAH population, treatment with the phosphodiesterase inhibitor sildenafil was associated with a dose-dependent rise in EPC numbers, resulting in levels consistently above those found with other therapies. CONCLUSIONS Circulating EPC numbers are reduced in 2 well-characterized forms of PAH, which also exhibit raised levels of inflammatory mediators. Sildenafil treatment may represent a pharmacological means of increasing circulating EPC numbers long-term.
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Affiliation(s)
- Gerhard-Paul Diller
- Adult Congenital Heart Centre and Centre for Pulmonary Hypertension, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK.
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Assessment of endothelial function in the patient with erectile dysfunction: an opportunity for the urologist. Int J Impot Res 2008; 20:370-7. [DOI: 10.1038/ijir.2008.13] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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