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Allen MS, Tostes RC. Cigarette smoking and erectile dysfunction: an updated review with a focus on pathophysiology, e-cigarettes, and smoking cessation. Sex Med Rev 2023. [DOI: 10.1093/sxmrev/qeac007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Abstract
Introduction
Cigarette smoking has major health implications and causes substantial damage to all organ systems. Approximately one-third of men are active smokers worldwide, and most men are unaware that cigarette smoking can contribute to erectile dysfunction (ED).
Objectives
This article aims to provide a comprehensive overview of research conducted on cigarette smoking and ED, with a particular focus on pathophysiology, electronic cigarettes (e-cigarettes), and smoking cessation.
Methods
A manual literature search was conducted on all research conducted on cigarette smoking and ED up to October 2022.
Results
Substantial evidence is now available showing that past and current cigarette smoking has dose-dependent associations with ED in studies controlling for age and important health comorbidities. Cigarette smoke contains nicotine, carbon monoxide, oxidant chemicals, and metals that can damage the endothelium and disrupt erectile processes. For current smokers, smoking abstinence can strengthen the endothelium and reverse diminished erectile function. The effect of e-cigarettes on endothelial damage and ED remains largely untested. E-cigarettes expose users to fine and ultrafine particles and toxins that can increase risk of cardiovascular injury, but these acute effects appear less potent than conventional cigarettes (long-term cardiovascular effects are still unknown). E-cigarettes are therefore likely to have less harmful effects on ED than conventional cigarettes.
Conclusions
Smoking cessation programs that focus on nicotine replacement therapy (transdermal patches, gum, or inhalers), behavioral counseling, social support, and education programs can be effective approaches to ED treatment in active smokers. Temporarily transferring from regular cigarettes to e-cigarettes—which transmit some of the same carcinogens as conventional cigarettes and are likely to have some long-term cardiovascular effects that disrupt erectile function—might also be useful for long-term smoking cessation and treatment of ED.
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Affiliation(s)
- Mark S Allen
- Department of Psychology and Therapeutic Studies , Leeds Trinity University, Leeds, LS18 5HD, UK
| | - Rita C Tostes
- Department of Pharmacology, University of São Paulo , São Paulo, Brazil
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Fernandes VS, López-Oliva ME, Martínez MP, Agis-Torres Á, Recio P, Navarro-Dorado J, Barahona MV, Benedito S, Prieto D, Climent B, Hernández M. In vitro inhibition of phosphodiesterase type 4 enhances rat corpus cavernosum nerve-mediated relaxation induced by gasotransmitters. Life Sci 2022; 296:120432. [PMID: 35219697 DOI: 10.1016/j.lfs.2022.120432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 02/16/2022] [Accepted: 02/21/2022] [Indexed: 11/15/2022]
Abstract
AIMS Nitric oxide (NO) and hydrogen sulfide (H2S) are involved in nerve-mediated corpus cavernosum (CC) relaxation. Expression of phosphodiesterase type 5 (PDE5) and type 4 (PDE4), cyclic guanosine monophosphate (cGMP)- and cyclic adenosine monophosphate (cAMP)-specific, respectively, has been described and PDE5- and PDE4-inhibitors induce cavernous smooth muscle relaxation. Whereas the NO/cGMP signaling pathway is well established in penile erection, the cAMP-mediated mechanism is not fully elucidated. The aim of this study is to investigate the localization and the functional significance of PDE4 in rat CC tone regulation. MAIN METHODS We performed immunohistochemistry for the detection of the PDE4A isoenzyme. Isometric tension recordings for roflumilast and tadalafil, PDE4 and PDE5 inhibitors, respectively, electrical field stimulation (EFS) and β-adrenoceptor agonist isoproterenol and endogenous H2S production measurement. KEY FINDINGS A marked PDE4A expression was detected mainly localized in the nerve cells of the cavernous smooth muscle. Furthermore, roflumilast and tadalafil exhibited strong corpus cavernous relaxations. Endogenous H2S production was decreased by NO and H2S synthase inhibitors and increased by roflumilast. Isoproterenol- and EFS-induced relaxations were increased by roflumilast. SIGNIFICANCE These results indicate that PDE4A is mainly expressed within the nerves cells of the rat CC, where roflumilast induces a potent corpus cavernous relaxation per se and potentiates the response induced by β-adrenoceptor activation. The fact that roflumilast enhances H2S production, as well as EFS-elicited responses suggests that PDE4 inhibitors modulate, in a positive feedback fashion, nerve-mediated relaxation induced by gasotransmitters, thus indicating a key role for neuronal PDE4 in penile erection.
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Affiliation(s)
- Vítor S Fernandes
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - María Elvira López-Oliva
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - María Pilar Martínez
- Departamento de Anatomía y Anatomía Patológica Comparadas, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Ángel Agis-Torres
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Paz Recio
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Jorge Navarro-Dorado
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - María Victoria Barahona
- Departamento de Farmacología y Toxicología, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Sara Benedito
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Dolores Prieto
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Belén Climent
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain.
| | - Medardo Hernández
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain.
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Functional reconstruction of injured corpus cavernosa using 3D-printed hydrogel scaffolds seeded with HIF-1α-expressing stem cells. Nat Commun 2020; 11:2687. [PMID: 32483116 PMCID: PMC7264263 DOI: 10.1038/s41467-020-16192-x] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 04/17/2020] [Indexed: 01/13/2023] Open
Abstract
Injury of corpus cavernosa results in erectile dysfunction, but its treatment has been very difficult. Here we construct heparin-coated 3D-printed hydrogel scaffolds seeded with hypoxia inducible factor-1α (HIF-1α)-mutated muscle-derived stem cells (MDSCs) to develop bioengineered vascularized corpora. HIF-1α-mutated MDSCs significantly secrete various angiogenic factors in MDSCs regardless of hypoxia or normoxia. The biodegradable scaffolds, along with MDSCs, are implanted into corpus cavernosa defects in a rabbit model to show good histocompatibility with no immunological rejection, support vascularized tissue ingrowth, and promote neovascularisation to repair the defects. Evaluation of morphology, intracavernosal pressure, elasticity and shrinkage of repaired cavernous tissue prove that the bioengineered corpora scaffolds repair the defects and recover penile erectile and ejaculation function successfully. The function recovery restores the reproductive capability of the injured male rabbits. Our work demonstrates that the 3D-printed hydrogels with angiogenic cells hold great promise for penile reconstruction to restore reproductive capability of males. Injury of corpus cavernosa results in erectile dysfunction, and repair leading to restoration of function is difficult. Here the authors construct 3D printed hydrogel constructs seeded with HIF-1α-expressing muscle derived stem cells to restore corpus function in a rabbit model.
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Ferrini MG, Abraham A, Nguyen S, Luna R, Flores M, Artaza JN, Graciano L, Rajfer J. Exogenous l-ARGININE does not stimulate production OF NO or cGMP within the rat corporal smooth muscle cells in culture. Nitric Oxide 2019; 89:64-70. [PMID: 31075315 DOI: 10.1016/j.niox.2019.05.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 05/04/2019] [Accepted: 05/06/2019] [Indexed: 02/01/2023]
Abstract
BACKGROUND AND AIM Nitric oxide (NO) is the intracellular chemical responsible for initiating a penile erection. Despite conflicting clinical data, it continues to be publicized and promoted that orally administered l-arginine, the putative substrate for NO, enhances the erectile response presumably by stimulating NO production by the corporal tissues resulting in an increase in cGMP production. To shed light on this issue, an in vitro study was conducted to explore the effect of direct exogenous administration of l-arginine as well as its precursor and metabolite, l-citrulline, on the NO-cGMP pathway within the cavernosal smooth muscle (CSM) cell. MATERIALS AND METHODS CSM cells obtained from 8 to 10 week old Sprague-Dawley rats were grown in Dulbecco media with 20% fetal calf serum and then incubated with or without l-arginine (L-ARG) or l-citrulline (L-CIT) in a time course and dose-response manner. Sildenafil (0.4 mM), IBMX (1 mM), l-NAME (3 μM), ODQ (5 μM) and Deta Nonoate (10 μM) were used as either inhibitors or stimulators of the NO-cGMP pathway. mRNA and protein were extracted and used for the determination of the phosphodiesterase 5 (PDE5). PDE5 activity was determined by luminometry. cGMP content was determined by ELISA. Nitrite formation, an indicator of NO production, was measured in the cell culture media by a colorimetric assay. The cationic (CAT-1) and neutral (SNAT-1) amino acid transporters for L-ARG and L-CIT, respectively, were determined by Western blot. RESULTS When compared to untreated CSM cells, incubation with 0.25-4.0 mM of L-ARG or 0.3-4.8 mM of L-CIT anywhere between 3 and 24 h did not result in any additional nitrite or cGMP production. The addition of l-NAME, IBMX or ODQ to these L-ARG and L-CIT treated cells did not alter these results. L-CIT but not L-ARG increased PDE5 mRNA and protein content as well as the activity of the PDE5 enzyme. Both CAT-1 and SNAT-1 were expressed in the CSM cells. CONCLUSIONS This in vitro study demonstrates that exogenous administration of L-ARG or L-CIT failed to stimulate production of either NO or cGMP by the corporal CSM cells. A re-evaluation of the presumptive role of the exogenous administration of L-ARG in improving the synthesis of NO at least at the level of the CSM cells appears warranted.
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Affiliation(s)
- Monica G Ferrini
- Department of Health and Life Sciences, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA; Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
| | - Andrea Abraham
- Department of Health and Life Sciences, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA
| | - Sabine Nguyen
- Department of Health and Life Sciences, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA
| | - Robert Luna
- Department of Health and Life Sciences, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA
| | - Manuel Flores
- Department of Health and Life Sciences, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA
| | - Jorge N Artaza
- Department of Health and Life Sciences, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA; Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Leslie Graciano
- Department of Health and Life Sciences, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA
| | - Jacob Rajfer
- Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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Penile constitutive nitric oxide synthase expression in rats exposed to unpredictable chronic mild stress: role of inflammation. Int J Impot Res 2016; 29:76-81. [DOI: 10.1038/ijir.2016.50] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Revised: 09/04/2016] [Accepted: 10/28/2016] [Indexed: 11/08/2022]
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Simonsen U, Comerma-Steffensen S, Andersson KE. Modulation of Dopaminergic Pathways to Treat Erectile Dysfunction. Basic Clin Pharmacol Toxicol 2016; 119 Suppl 3:63-74. [DOI: 10.1111/bcpt.12653] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 08/16/2016] [Indexed: 12/14/2022]
Affiliation(s)
- Ulf Simonsen
- Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology; Aarhus University; Aarhus C Denmark
| | - Simon Comerma-Steffensen
- Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology; Aarhus University; Aarhus C Denmark
- Department of Biomedical Science; Faculty of Veterinary Science; Central University of Venezuela; Maracay Bolivarian Republic of Venezuela
| | - Karl-Erik Andersson
- Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology; Aarhus University; Aarhus C Denmark
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Suzuki E, Nishimatsu H, Oba S, Takahashi M, Homma Y. Chronic kidney disease and erectile dysfunction. World J Nephrol 2014; 3:220-229. [PMID: 25374815 PMCID: PMC4220354 DOI: 10.5527/wjn.v3.i4.220] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 06/22/2014] [Accepted: 09/10/2014] [Indexed: 02/05/2023] Open
Abstract
Erectile dysfunction (ED) is a common condition among male chronic kidney disease (CKD) patients. Its prevalence is estimated to be approximately 80% among these patients. It has been well established that the production of nitric oxide from the cavernous nerve and vascular endothelium and the subsequent production of cyclic GMP are critically important in initiating and maintaining erection. Factors affecting these pathways can induce ED. The etiology of ED in CKD patients is multifactorial. Factors including abnormalities in gonadal-pituitary system, disturbance in autonomic nervous system, endothelial dysfunction, anemia (and erythropoietin deficiency), secondary hyperparathyroidism, drugs, zinc deficiency, and psychological problems are implicated in the occurrence of ED. An improvement of general conditions is the first step of treatment. Sufficient dialysis and adequate nutritional intake are necessary. In addition, control of anemia and secondary hyperparathyroidism is required. Changes of drugs that potentially affect erectile function may be necessary. Further, zinc supplementation may be necessary when zinc deficiency is suspected. Phosphodiesterase type 5 inhibitors (PDE5Is) are commonly used for treating ED in CKD patients, and their efficacy was confirmed by many studies. Testosterone replacement therapy in addition to PDE5Is may be useful, particularly for CKD patients with hypogonadism. Renal transplantation may restore erectile function. ED is an early marker of cardiovascular disease (CVD), which it frequently precedes; therefore, it is crucial to examine the presence of ED in CKD patients not only for the improvement of the quality of life but also for the prevention of CVD attack.
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Abstract
Erectile dysfunction (ED) has an adverse impact on men's quality of life. Penile erection, which is regulated by nerves that are innervated into the erectile tissue, can be affected by functional or anatomical trauma of the perineal region, including specific structures of the penis, causing ED. Penile erection is neurologically controlled by the autonomic nervous system. Therefore, it is of utmost importance to understand the neurogenic structure of the erectile tissue and the types of neurotransmitters involved in the penile erection process. Here, we highlight the basic clinical anatomy and erectile function of the penis. Understanding the clinical connotation of the relationship between penile erectile structure and function may provide fresh insights for identifying the main mechanisms involved in ED and help develop surgical techniques for the treatment of ED.
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Rajfer J, Miner MM. Hypertension: The Link Between Erectile Dysfunction and Coronary Artery Disease. JOURNAL OF MEN'S HEALTH 2013. [DOI: 10.1089/jomh.2013.1503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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Abstract
INTRODUCTION A role for cytokines in the pathophysiology of erectile dysfunction (ED) has emerged. Cytokines induce genes that synthesize other peptides in the cytokine family and several mediators, such as prostanoids, leukotrienes, nitric oxide, bradykinin, reactive oxygen species, and platelet-activating factor, all of which can affect vascular function. Consistent with the fact that the cavernosal tissue is a complex extension of the vasculature, risk factors that affect the vasculature have been shown to affect cavernosal function as well. Accordingly, the penile tissue has been recognized as an early sentinel for atherosclerosis that underlies coronary artery disease and cardiovascular diseases (CVD). AIM To review the literature pertaining to the role of tumor necrosis factor-alpha (TNF-α) in ED. METHODS PubMed search for pertinent publications on the role of cytokines, particularly TNF-α, in CVD and ED. MAIN OUTCOME MEASURES Clinical and experimental evidence demonstrates that TNF-α may play a role in ED. RESULTS TNF-α has been shown to play an important role in CVD, mainly due to its direct effects on the vasculature. In addition, high levels of TNF-α were demonstrated in patients with ED. In this review, we present a short description of the physiology of erection and the cytokine network. We focus on vascular actions of TNF-α that support a role for this cytokine as a potential candidate in the pathophysiology of ED, particularly in the context of CVD. A brief overview of its discovery, mechanisms of synthesis, receptors, and its main actions on the systemic and penile vasculature is also presented. CONCLUSIONS Considering that ED results from a systemic arterial defect not only confined to the penile vasculature, implication of TNF-α in the pathophysiology of ED offers a humoral linking between CVD and ED.
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11
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Nitric oxide neurons and neurotransmission. Prog Neurobiol 2010; 90:246-55. [DOI: 10.1016/j.pneurobio.2009.10.007] [Citation(s) in RCA: 141] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2008] [Revised: 04/22/2009] [Accepted: 10/09/2009] [Indexed: 11/24/2022]
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Tostes RC, Carneiro FS, Lee AJ, Giachini FRC, Leite R, Osawa Y, Webb RC. Cigarette smoking and erectile dysfunction: focus on NO bioavailability and ROS generation. J Sex Med 2008; 5:1284-95. [PMID: 18331273 DOI: 10.1111/j.1743-6109.2008.00804.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Thirty million men in the United States suffer from erectile dysfunction (ED) and this number is expected to double by 2025. Considered a major public health problem, which seriously affects the quality of life of patients and their partners, ED becomes increasingly prevalent with age and chronic smoking is a major risk factor in the development of ED. AIM To review available evidence concerning the effects of cigarette smoking on vascular changes associated with decreased nitric oxide (NO) bioavailability and increased reactive oxygen species (ROS) generation. METHODS We examined epidemiological and clinical data linking cigarette smoking and ED, and the effects of smoking on vascular NO bioavailability and ROS generation. MAIN OUTCOME MEASURES There are strong parallels between smoking and ED and considerable evidence supporting the concept that smoking-related ED is associated with reduced bioavailability of NO because of increased ROS. RESULTS Cigarette smoking-induced ED in human and animal models is associated with impaired arterial flow to the penis or acute vasospasm of the penile arteries. Long-term smoking produces detrimental effects on the vascular endothelium and peripheral nerves and also causes ultrastructural damage to the corporal tissue, all considered to play a role in chronic smoking-induced ED. Clinical and basic science studies provide strong indirect evidence that smoking may affect penile erection by the impairment of endothelium-dependent smooth muscle relaxation or more specifically by affecting NO production via increased ROS generation. Whether nicotine or other products of cigarette smoke mediate all effects related to vascular damage is still unknown. CONCLUSIONS Smoking prevention represents an important approach for reducing the risk of ED. The characterization of the components of cigarette smoke leading to ED and the mechanisms by which these components alter signaling pathways activated in erectile responses are necessary for a complete comprehension of cigarette smoking-associated ED.
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Affiliation(s)
- Rita C Tostes
- University of Sao Paulo, Department of Pharmacology, Sao Paulo, SP, Brazil.
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Carneiro FS, Giachini FRC, Lima VV, Carneiro ZN, Leite R, Inscho EW, Tostes RC, Webb RC. Adenosine actions are preserved in corpus cavernosum from obese and type II diabetic db/db mouse. J Sex Med 2008; 5:1156-1166. [PMID: 18221284 DOI: 10.1111/j.1743-6109.2007.00752.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Erectile dysfunction (ED) in diabetes is associated with autonomic neuropathy and endothelial dysfunction. Whereas the nonadrenergic-noncholinergic (NANC)/neurogenic nitric oxide pathway has received great attention in diabetes-associated ED, few studies have addressed sympathetic overactivity. AIM To test the hypothesis that adenosine-induced inhibition of adrenergic-mediated contractile responses in mouse corpus cavernosum is impaired in the presence of diabetes. METHODS The db/db (obesity and type II diabetes caused by a leptin receptor mutation) mouse strain was used as a model of obesity and type II diabetes, and standard procedures were performed to evaluate functional cavernosal responses. MAIN OUTCOME MEASURES Increased cavernosal responses to sympathetic stimulation in db/db mice are not associated with impaired prejunctional actions of adenosine. RESULTS Electrical field stimulation (EFS)-, but not phenylephrine (PE)-, induced contractions are enhanced in cavernosal strips from db/db mice in comparison with those from lean littermates. Direct effects of adenosine, 2-chloro-adenosine, A(1) receptor agonist C-8031 (N6 cyclopentyladenosine), and sodium nitroprusside are similar between the strips from lean and db/db mice, whereas relaxant responses to acetylcholine and NANC stimulation are significantly impaired in the cavernosal strips from db/db mice. 5'-Iodotubercidin (adenosine kinase inhibitor) and dipyridamole (inhibitor of adenosine transport), as well as the A(1) agonist C-8031, significantly and similarly inhibit contractions induced by stimulation of adrenergic nerves in the cavernosal strips from lean and db/db mice. CONCLUSIONS Results from this study suggest that corpora cavernosa from obese and diabetic db/db mice display altered neural-mediated responses that would favor penile detumescence, i.e., increased contractile response to adrenergic nerve stimulation and decreased relaxant responses upon activation of NANC nerves. However, increased cavernosal responses to adrenergic nerve stimulation are not due to impaired negative modulation of sympathetic neurotransmission by adenosine in this diabetic model.
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Affiliation(s)
- Fernando Silva Carneiro
- Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil;; Department of Physiology, Medical College of Georgia, Augusta, GA, USA.
| | - Fernanda R C Giachini
- Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil;; Department of Physiology, Medical College of Georgia, Augusta, GA, USA
| | - Victor V Lima
- Department of Physiology, Medical College of Georgia, Augusta, GA, USA
| | | | - Romulo Leite
- Department of Physiology, Medical College of Georgia, Augusta, GA, USA
| | - Edward W Inscho
- Department of Physiology, Medical College of Georgia, Augusta, GA, USA
| | - Rita C Tostes
- Department of Physiology, Medical College of Georgia, Augusta, GA, USA; Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil
| | - R Clinton Webb
- Department of Physiology, Medical College of Georgia, Augusta, GA, USA
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Abstract
Recent experimental evidence suggests that arterial insufficiency precedes the structural and functional changes in corpora cavernosa (CC) leading to organic erectile dysfunction (ED). The present review gives an overview of the physiological factors involved in the regulation of penile vasculature. Sympathetic nerves maintain flaccidity and tonically released noradrenaline induces vasoconstriction of both arteries and veins through alpha(1)- and alpha(2)-postsynaptic receptors and downregulates its own release and that of nitric oxide (NO) through alpha(2)-presynaptic receptors. The sympathetic cotransmitter neuropeptide Y (NPY) modulates noradrenergic vasoconstriction in penile small arteries by both enhancing and depressing noradrenaline contractions through Y(1)- and Y(2)-postsynaptic and a NO-independent atypical endothelial receptor, respectively. Activation of alpha(1)-adrenoceptors involves both Ca(2+) influx through L-type and receptor-operated Ca(2+) channels (ROC) and Ca(2+) sensitization mechanisms mediated by protein kinase C (PKC), tyrosine kinases (TKs) and Rho kinase (RhoK). In addition, RhoK can regulate Ca(2+) entry in penile arteries upon receptor stimulation. Vasodilatation of penile arteries and large veins during erection is mediated by neurally released NO. The subsequent increased arterial inflow to the cavernosal sinoids and shear stress on the endothelium lining penile arteries activates endothelial NO production through Akt phosphorylation of endothelial NO synthase (eNOS). NO stimulates guanylate cyclase and increased cyclic guanin 3'-monophosphate (cGMP) levels in turn activate protein kinase G (PKG), which enhances K(+) efflux through Ca(2+)-activated (K(Ca)) and voltage-dependent Ca(2+) (K(v)) channels in penile arteries and veins, respectively. PKG-mediated decrease in Ca(2+) sensitivity and its regulation by RhoK remains to be clarified in penile vasculature. Phosphodiesterase type 5 (PDE5) inhibitors are potent vasodilators of penile resistance arteries and increase the content and effects of basally released endothelial NO. Endothelium-dependent relaxations of penile small arteries also include an endothelium-derived hyperpolarizing factor (EDHF)-type response, which is impaired in diabetes and hypertension-associated ED. Locally produced contractile and relaxant prostanoids regulate penile venous and arterial tone, respectively. The latter activates prostaglandin I (IP) and prostaglandin E (EP) receptors coupled to adenylate cyclase and to the increase of cyclic adenosine monophosphate (cAMP) levels, which in turn stimulates K(+) efflux through ATP-sensitive K(+) (K(ATP)) channels. There is a crosstalk between the cGMP and cAMP signaling pathways in penile small arteries. Relevant issues such as the mechanisms underlying the excitation-secretion coupling of the endothelial cells, as well as those involved in cell proliferation and vascular remodeling of the penile vasculature remain to be elucidated. In addition, only few studies have investigated the changes in structure and function of penile arteries in cardiovascular risk situations leading to ED.
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Affiliation(s)
- D Prieto
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
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15
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Purves-Tyson T, Arshi M, Handelsman DJ, Cheng Y, Keast JR. Androgen and estrogen receptor-mediated mechanisms of testosterone action in male rat pelvic autonomic ganglia. Neuroscience 2007; 148:92-104. [PMID: 17629410 PMCID: PMC2012365 DOI: 10.1016/j.neuroscience.2007.05.043] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2006] [Revised: 04/30/2007] [Accepted: 05/01/2007] [Indexed: 02/05/2023]
Abstract
Although male reproductive function is primarily androgen dependent, many studies suggest that estrogens have direct actions on the male reproductive organs. Pelvic autonomic neurons provide the motor control of the internal reproductive organs and the penis and various properties of these neurons are affected by endogenous androgens. However, the possible role of estrogens at this site has not been examined. Here we have investigated the significance of estrogens produced by aromatization of testosterone (T) in the physiological actions of androgens on adult male rat pelvic ganglion neurons. Reverse transcriptase polymerase chain reaction (RT-PCR) studies showed that aromatase and both estrogen receptors (ERalpha and ERbeta) are expressed in these ganglia. Western blotting also showed that aromatase is expressed in male pelvic ganglia. Using immunohistochemical visualization, ERalpha was predominantly expressed by nitric oxide synthase (NOS)-positive parasympathetic pelvic ganglion neurons. In vivo studies showed that the decrease in pelvic ganglion soma size caused by gonadectomy could be prevented by administration of T or dihydrotestosterone (DHT), but not 17beta-estradiol (E2), showing that this maintenance action of testosterone is mediated entirely by androgenic mechanisms. However, in vitro studies of cultured pelvic ganglion neurons revealed that T, DHT and E each stimulated the growth of longer and more complex neurites in both noradrenergic and cholinergic NOS-expressing neurons. The effects of T were attenuated by either androgen or estrogen receptor antagonists, or by inhibition of aromatase. Together these studies demonstrate that estrogens are likely to be synthesized in the male pelvic ganglia, produced from T by local aromatase. The effects of androgens on axonal growth are likely to be at least partly mediated by estrogenic mechanisms, which may be important for understanding disease-, aging- and injury-induced plasticity in this part of the nervous system.
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MESH Headings
- Androgen Antagonists/pharmacology
- Animals
- Aromatase/metabolism
- Cell Enlargement/drug effects
- Cells, Cultured
- Dihydrotestosterone/pharmacology
- Estrogen Antagonists/pharmacology
- Estrogen Receptor alpha/metabolism
- Estrogen Receptor beta/metabolism
- Estrogens/biosynthesis
- Ganglia, Autonomic/drug effects
- Ganglia, Autonomic/metabolism
- Ganglia, Parasympathetic/drug effects
- Ganglia, Parasympathetic/metabolism
- Genitalia, Male/innervation
- Genitalia, Male/physiology
- Hypogastric Plexus/drug effects
- Hypogastric Plexus/metabolism
- Male
- Nitrergic Neurons/drug effects
- Nitrergic Neurons/metabolism
- Nitric Oxide Synthase/metabolism
- RNA, Messenger/drug effects
- RNA, Messenger/metabolism
- Rats
- Rats, Wistar
- Receptors, Androgen/drug effects
- Receptors, Androgen/metabolism
- Receptors, Estrogen/drug effects
- Receptors, Estrogen/metabolism
- Testosterone/metabolism
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Affiliation(s)
- T.D. Purves-Tyson
- Pain Management Research Institute, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
- Prince of Wales Medical Research Institute and University of New South Wales, Barker Street, Randwick, NSW 2031 Australia
| | - M.S. Arshi
- Pain Management Research Institute, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | | | - Y. Cheng
- Pain Management Research Institute, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - J. R. Keast
- Pain Management Research Institute, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
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Hallén K, Wiklund NP, Gustafsson LE. Inhibitors of phosphodiesterase 5 (PDE 5) inhibit the nerve-induced release of nitric oxide from the rabbit corpus cavernosum. Br J Pharmacol 2006; 150:353-60. [PMID: 17179943 PMCID: PMC2013895 DOI: 10.1038/sj.bjp.0706991] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND AND PURPOSE Nitrergic neurons are important for erectile responses in the corpus cavernosum and impaired signalling results in erectile dysfunction, today treated successfully by oral administration of the selective phosphodiesterase 5 (PDE 5) inhibitors sildenafil, tadalafil and vardenafil. Although the importance of nitrergic neurons in urogenital function has become evident, it has not been investigated if the PDE 5 inhibitors affect the nerve-induced release of nitric oxide (NO). In a previous study we found that the soluble guanylate cyclase (sGC)/cyclic guanosine 3',5'-monophosphate (cGMP) pathway might modulate nerve-induced release of NO in isolated cavernous tissue. EXPERIMENTAL APPROACH Electrical field stimulation (EFS 5 Hz, 40 V, 0.3 ms pulse duration, 25 pulses at intervals of 2 min) of rabbit isolated cavernous tissue elicited reproducible, nerve-mediated relaxations in the presence of scopolamine (10(-5) M), guanethidine (10(-5) M) and phenylephrine (3 x 10(-6) M). In superfusion experiments, nerve stimulation (20 Hz, 40 V, 1 ms) of the cavernous tissue evoked release of NO/NO2-, measured by chemiluminescence. KEY RESULTS Sildenafil, tadalafil and vardenafil decreased the muscular tone and prolonged the relaxations to nerve stimulation. The evoked release of NO decreased to 72+/-11%, 55+/-16% and 61+/-14% of control, respectively after addition of sildenafil, tadalafil or vardenafil (all 10(-4) M, n=6-8, p<0.05). CONCLUSIONS AND IMPLICATIONS Selective PDE 5 inhibitors influence the nerve-induced release of NO, probably via cGMP-mediated negative feedback. This negative feedback might explain why priapism is not seen during monotherapy with the PDE inhibitors.
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Affiliation(s)
- K Hallén
- Department of Molecular Medicine and Surgery, Section of Urology, Karolinska Hospital, Stockholm, Sweden.
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17
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Sáenz de Tejada I, Angulo J, Cellek S, González-Cadavid N, Heaton J, Pickard R, Simonsen U. Physiology of erectile function. J Sex Med 2006; 1:254-65. [PMID: 16422955 DOI: 10.1111/j.1743-6109.04038.x] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
INTRODUCTION There are numerous investigations concerning the balance and interactions between relaxant and contractile factors regulating penile smooth muscle (arterial and trabecular) tone, the determinant of penile flaccidity or erection. Enhanced knowledge of erectile physiology may improve management of men with erectile dysfunction. Aim. To provide state-of-the-art knowledge on the physiology of erectile function. METHODS An international consultation in collaboration with the major urology and sexual medicine associations assembled over 200 multidisciplinary experts from 60 countries into 17 committees. Committee members established specific objectives and scopes for various male and female sexual medicine topics. The recommendations concerning state-of-the-art knowledge in the respective sexual medicine topic represent the opinion of experts from five continents developed in a process over a two-year period. Concerning the physiology of erectile function and pathophysiology of erectile dysfunction committee, there were seven experts from five countries. MAIN OUTCOME MEASURE Expert opinion was based on the grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate. RESULTS Key roles in the mechanism determining the tone of penile smooth muscle are played by the rise of the intracellular concentration of free calcium and the sensitivity of the contractile machinery to calcium, endothelial health, endothelium-derived nitric oxide, endothelium-derived hyperpolarizing factor (EDHF), neuronal nitric oxide, cyclic guanosine monophosphate-dependent protein kinase and phosphodiesterase type 5. CONCLUSIONS A number of new mechanisms have been identified for the local regulation of penile smooth muscle contractility and therefore penile erection. Molecules participating in these pathways can be considered targets for the development of new treatments to treat erectile dysfunction.
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Teixeira CE, Ying Z, Webb RC. Proerectile effects of the Rho-kinase inhibitor (S)-(+)-2-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]homopiperazine (H-1152) in the rat penis. J Pharmacol Exp Ther 2005; 315:155-62. [PMID: 15976017 DOI: 10.1124/jpet.105.086041] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The Rho-kinase pathway mediates Ca2+ sensitization in the penile circulation, which maintains the penis in the flaccid state. We aimed to investigate the functional effect of a novel Rho-kinase inhibitor, H-1152 [(S)-(+)-2-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]homopiperazine], both in vitro and in vivo as well as to demonstrate the expression of Rho guanine nucleotide exchange factors (RhoGEFs) in the rat corpus cavernosum (CC), by using a semiquantitative reverse transcription-polymerase chain reaction assay to measure their mRNA expression. Cumulative addition of H-1152 (0.001-3 microM) or Y-27632 [0.01-30 microM; (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide] caused sustained relaxations of precontracted CC strips, which were not affected by inhibition of the nitric oxide signaling pathway. Addition of H-1152 (0.1 microM), Y-27632 (1 microM), or sodium nitroprusside (SNP; 0.1 microM) caused rightward shifts in the curves to phenylephrine (PE), but it had little effect on the contractions mediated by electrical field stimulation (EFS). It is noteworthy that when H-1152 or Y-27632 was combined with SNP, a marked synergistic inhibition was noted both on PE- and EFS-induced contractions. Intraperitoneal administration of H-1152 (100 nmol/kg) had a discrete effect on mean arterial pressure and significantly enhanced erectile responses evoked by stimulation of the cavernous nerve. The mRNA expression for PDZ-RhoGEF, p115RhoGEF, and leukemia-associated RhoGEF in cavernosal segments was visualized by electrophoresis on agarose gel. The results indicate that H-1152 is a powerful Rho-kinase inhibitor, giving rise to its therapeutic potential in the treatment of erectile dysfunction. The regulator of G-protein signaling-containing RhoGEFs may represent key components of the molecular mechanisms associated with the abnormal function of the cavernosal smooth muscle.
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Affiliation(s)
- Cleber E Teixeira
- Department of Physiology, Medical College of Georgia, 1120 15th St., CA-3101, Augusta, GA 30912-3000, USA.
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19
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Dorfman VB, López-Costa JJ, Vega C, Bayona JC, Capani F, Fabián Loidl C, Coirini H. Changes of NADPH-diaphorase reactivity in lumbar spinal cord of short-term streptozotocin induced diabetic rats. Brain Res 2004; 997:185-93. [PMID: 14706871 DOI: 10.1016/j.brainres.2003.10.038] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Diabetes is an endocrine and metabolic disorder often associated with erectile dysfunction and peripheral neuropathy. Among other factors, penile erection is induced by activation of nitric oxide synthase (NOS). Hypothalamic paraventricular nuclei neurons produce NO and project to spinal cord areas implicated in penile reflexes. These nuclei have shown an increase of NOS in streptozotocin-induced diabetic rats. NOS-containing neurons are identical to the populations of neurons selectively stained for NADPH-diaphorase activity. Using this technique, we have evaluated changes of NOS in the lumbar spinal cord of diabetic rats with or without insulin treatment. Positive staining was found in motoneurons, dorsal horn neurons (layer II), neurons surrounding the ependimus (layer X) and neurons at the intermediolateral cell column (ILCC). Diabetic animals showed significant decrease in reactive area and increase of the histochemical reaction in motoneurons from the sexual dimorphic nuclei and in neurons of the ILCC. A marked decrease of the number of reactive neurons was also observed in layer II. Morphologic alterations were observed in neurons of layer X as an increase in the percentage of multipolar neurons and a decrease in the number and length of secondary processes. The alterations observed in these animals were absent in the insulin treated diabetic animals. These results show the plasticity of lumbar spinal cord neurons, suggesting a direct participation of NO synthesis in the physiopathology of the erection dysfunction in diabetes.
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Affiliation(s)
- Verónica Berta Dorfman
- Laboratorio de Neurobiología, Instituto de Biología y Medicina Experimental, V. de Obligado 2490, C1428AND, Ciudad Autónoma de Buenos Aires, Argentina
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20
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Toda N, Okamura T. The pharmacology of nitric oxide in the peripheral nervous system of blood vessels. Pharmacol Rev 2003; 55:271-324. [PMID: 12773630 DOI: 10.1124/pr.55.2.3] [Citation(s) in RCA: 223] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Unanticipated, novel hypothesis on nitric oxide (NO) radical, an inorganic, labile, gaseous molecule, as a neurotransmitter first appeared in late 1989 and into the early 1990s, and solid evidences supporting this idea have been accumulated during the last decade of the 20th century. The discovery of nitrergic innervation of vascular smooth muscle has led to a new understanding of the neurogenic control of vascular function. Physiological roles of the nitrergic nerve in vascular smooth muscle include the dominant vasodilator control of cerebral and ocular arteries, the reciprocal regulation with the adrenergic vasoconstrictor nerve in other arteries and veins, and in the initiation and maintenance of penile erection in association with smooth muscle relaxation of the corpus cavernosum. The discovery of autonomic efferent nerves in which NO plays key roles as a neurotransmitter in blood vessels, the physiological roles of this nerve in the control of smooth muscle tone of the artery, vein, and corpus cavernosum, and pharmacological and pathological implications of neurogenic NO have been reviewed. This nerve is a postganglionic parasympathetic nerve. Mechanical responses to stimulation of the nerve, mainly mediated by NO, clearly differ from those to cholinergic nerve stimulation. The naming "nitrergic or nitroxidergic" is therefore proposed to avoid confusion of the term "cholinergic nerve", from which acetylcholine is released as a major neurotransmitter. By establishing functional roles of nitrergic, cholinergic, adrenergic, and other autonomic efferent nerves in the regulation of vascular tone and the interactions of these nerves in vivo, especially in humans, progress in the understanding of cardiovascular dysfunctions and the development of pharmacotherapeutic strategies would be expected in the future.
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Affiliation(s)
- Noboru Toda
- Toyama Institute for Cardiovascular Pharmacology Research, Toyama Bldg., 7-13, 1-Chome, Azuchi-machi, Chuo-ku, Osaka 541-0052, Japan.
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21
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Bagcivan I, Kilicarslan H, Sarac B, Gokce G, Yildirim S, Ayan S, Sarioglu Y. The evaluation of the effects of renal failure on erectile dysfunction in a rabbit model of chronic renal failure. BJU Int 2003; 91:697-701. [PMID: 12699488 DOI: 10.1046/j.1464-410x.2003.04179.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To determine whether chronic renal failure (CRF) reduces nitrergic relaxant responses in a rabbit model. MATERIALS AND METHODS Ten rabbits underwent surgery to induce uraemia (CRF rabbits) and a further 10 a sham operation (controls). Corpus cavernosal tissue was prepared and used in organ-chamber experiments, with relaxation assessed against a background of pre-contraction with phenylephrine. At the plateau of contraction, relaxation responses to cumulative concentrations of carbachol or sodium nitroprusside (SNP), to test endothelium-dependent and -independent relaxations, respectively, were assessed. Before electrical-field stimulation (EFS), the tissue was treated with an adrenergic nerve blocker and a muscarinic receptor blocker to eliminate the adrenergic and cholinergic components, and to determine the relaxation responses to the stimulation of nonadrenergic, noncholinergic (NANC) nerves. The relaxation responses in corporal strips obtained from CRF rabbits were compared with those from controls. RESULTS When tissues were contracted with KCl, tensions were similar in all groups. The impairment in concentration-dependent relaxation with carbachol was significant in CRF rabbits, but SNP- and papaverine-induced concentration-dependent relaxation responses were no different among the groups. EFS-induced frequency-dependent relaxations were significantly lower in CRF rabbits than in controls. CONCLUSION CRF inhibits the NANC-mediated relaxation of rabbit corpus cavernosum smooth muscle. Changes in NANC-mediated and carbachol-induced (endothelium-dependent) relaxation of corporal smooth muscle in the rabbit are probably caused by uraemia and subsequently, hyperthyroidism, hyperparathyroidism or low testosterone levels in CRF. These results also suggest that if vasoactive agents are to be used for treating erectile dysfunction in uraemic patients, direct-acting vasodilators and phosphodiesterase inhibitors will be useful.
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Affiliation(s)
- I Bagcivan
- Department of Urology, Medical Faculty, Cumhuriyet University, Sivas, Turkey
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22
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Maas R, Schwedhelm E, Albsmeier J, Böger RH. The pathophysiology of erectile dysfunction related to endothelial dysfunction and mediators of vascular function. Vasc Med 2002; 7:213-25. [PMID: 12553745 DOI: 10.1191/1358863x02vm429ra] [Citation(s) in RCA: 146] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The incidence of erectile dysfunction increases with diabetes, hypertension, hypercholesterolaemia, cardiovascular disease and renal failure. All these conditions are associated with endothelial dysfunction. This review addresses the pathophysiology of erectile dysfunction with a special focus on new insights into nitric oxide (NO)-mediated pathways, oxidative stress and parallels to endothelial dysfunction. NO appears to be the key mediator promoting endothelium-derived vasodilation and penile erection. The possibility is discussed that elevated plasma concentrations of asymmetrical dimethylarginine (ADMA), an endogenous NO synthase inhibitor, may provide an additional pathomechanism for various forms of erectile dysfunction associated with cardiovascular risk factors and disease. Likewise, the role of endothelium-derived factors mediating NO-independent pathways is evaluated.
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Affiliation(s)
- Renke Maas
- Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
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24
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MIZUSAWA H, HEDLUND P, BRIONI J, SULLIVAN J, ANDERSSON KE. Nitric Oxide Independent Activation of Guanylate Cyclase by YC-1 Causes Erectile Responses in the Rat. J Urol 2002. [DOI: 10.1016/s0022-5347(05)65142-7] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- H. MIZUSAWA
- From the Department of Clinical Pharmacology, University of Lund, Sweden, and Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois
| | - P. HEDLUND
- From the Department of Clinical Pharmacology, University of Lund, Sweden, and Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois
| | - J.D. BRIONI
- From the Department of Clinical Pharmacology, University of Lund, Sweden, and Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois
| | - J.P. SULLIVAN
- From the Department of Clinical Pharmacology, University of Lund, Sweden, and Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois
| | - K.-E. ANDERSSON
- From the Department of Clinical Pharmacology, University of Lund, Sweden, and Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois
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25
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Hurt KJ, Musicki B, Palese MA, Crone JK, Becker RE, Moriarity JL, Snyder SH, Burnett AL. Akt-dependent phosphorylation of endothelial nitric-oxide synthase mediates penile erection. Proc Natl Acad Sci U S A 2002; 99:4061-6. [PMID: 11904450 PMCID: PMC122648 DOI: 10.1073/pnas.052712499] [Citation(s) in RCA: 278] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/31/2001] [Indexed: 01/17/2023] Open
Abstract
In the penis, nitric oxide (NO) can be formed by both neuronal NO synthase and endothelial NOS (eNOS). eNOS is activated by viscous drag/shear stress in blood vessels to produce NO continuously, a process mediated by the phosphatidylinositol 3-kinase (PI3kinase)/Akt pathway. Here we show that PI3-kinase/Akt physiologically mediates erection. Both electrical stimulation of the cavernous nerve and direct intracavernosal injection of the vasorelaxant drug papaverine cause rapid increases in phosphorylated (activated) Akt and eNOS. Phosphorylation is diminished by wortmannin and LY294002, inhibitors of PI3-kinase, the upstream activator of Akt. The two drugs also reduce erection. Penile erection elicited by papaverine is reduced profoundly in mice with targeted deletion of eNOS. Our findings support a model in which rapid, brief activation of neuronal NOS initiates the erectile process, whereas PI3-kinase/Akt-dependent phosphorylation and activation of eNOS leads to sustained NO production and maximal erection.
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Affiliation(s)
- K Joseph Hurt
- Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA
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Mizusawa H, Hedlund P, Håkansson A, Alm P, Andersson KE. Morphological and functional in vitro and in vivo characterization of the mouse corpus cavernosum. Br J Pharmacol 2001; 132:1333-41. [PMID: 11250885 PMCID: PMC1572671 DOI: 10.1038/sj.bjp.0703938] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
1. In normal mice, the distribution of adrenergic, cholinergic, some peptidergic, and neuronal nitric oxide synthase (nNOS)-containing nerves were investigated. Functional in vitro correlates were obtained. An in vivo model was developed in which erectile haemodynamics in response to drugs or nerve-stimulation were studied. 2. Immunoreactivities for vesicular acetylcholine transporter protein (VAChT), nNOS-, and vasoactive intestinal polypeptide (VIP), co-existed in nerve fibres and terminal varicosities. Immunoreactivities for neuropeptide Y (NPY) and tyrosine hydroxylase (TH) were found in the same nerve structures. 3. Chemical sympathectomy abolished TH- and NPY-IR nerve structures in cavernous smooth muscle bundles. The distribution of calcitonin gene-related peptide (CGRP)-, nNOS-, VAChT- and VIP-IR nerve structures was unchanged. 4. In endothelial cells of the central and helicine arteries, veins and venules, intense immunoreactivity for endothelial NOS (eNOS) was observed. No distinct eNOS-IR cells were found lining the cavernous sinusoids. 5. In vitro, nerve-induced relaxations were verified, and endothelial NO/cyclic GMP-mediated relaxant responses were established. VIP and CGRP had small relaxant effects. A functioning adenylate cyclase/cyclic AMP pathway was confirmed. 6. Neuronal excitatory responses were abolished by prazosin, or forskolin. VIP and CGRP counteracted contractions, whereas NPY and scopolamine enhanced excitatory responses. 7. In vivo, erectile responses were significantly attenuated by L-NAME (50 mg kg(-1)) and facilitated by sildenafil (200 microg kg(-1)). 8. It is concluded that the mouse is a suitable model for studies of erectile mechanisms in vitro and in vivo.
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Affiliation(s)
- Hiroya Mizusawa
- Department of Clinical Pharmacology, University of Lund, Sweden
| | - Petter Hedlund
- Department of Clinical Pharmacology, University of Lund, Sweden
- Author for correspondence:
| | - Anders Håkansson
- Department of Microbiology, Immunology and Glycobiology, University of Lund, Sweden
| | - Per Alm
- Department of Pathology, University of Lund, Sweden
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Abstract
The functional state of the penis, flaccid or erect is governed by smooth muscle tone. Sympathetic contractile factors maintain flaccidity whilst parasympathetic factors induce smooth muscle relaxation and erection. It is generally accepted that nitric oxide (NO) is the principal agent responsible for relaxation of penile smooth muscle. NO is derived from two principal sources: directly from non-adrenergic non-cholinergic parasympathetic nerves and indirectly from the endothelium lining cavernosal sinusoids and blood vessels in response to cholinergic stimulation. The generation of NO from L-arginine is catalysed by nitric oxide synthase (NOS). There has been controversy over the relative prevalence of endothelial or neuronal NOS within the penis of different animal species. This review examines the role of NO in the penis in detail. Established and new treatments for erectile dysfunction whose effects are mediated via manipulation of the NO pathway are also described.
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Affiliation(s)
- J Cartledge
- The Pyrah Department of Urology, St James's University Hospital, Beckett Street, Leeds, LS18 4AW, UK.
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28
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Hedlund P, Ny L, Alm P, Andersson KE. Cholinergic nerves in human corpus cavernosum and spongiosum contain nitric oxide synthase and heme oxygenase. J Urol 2000. [PMID: 10953170 DOI: 10.1016/s0022-5347(05)67329-6] [Citation(s) in RCA: 73] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
PURPOSE To characterize the distribution of cholinergic nerves in the human corpus cavernosum (CC) and spongiosum (CS) using antibodies to the vesicular acetylcholine transporter (VAChT), and to compare this distribution to those of other transmitters/mediators or transmitter/mediator generating enzymes (heme oxygenases: HO-1 and HO-2; neuronal and endothelial NO synthases: nNOS and eNOS; vasoactive intestinal polypeptide: VIP; and tyrosine hydroxylase: TH), and to investigate NO- and carbon monoxide (CO)-mediated effects. MATERIALS AND METHODS Immunocytochemistry, confocal laser scanning microscopy, radioimmunoassay, and functional in vitro studies. RESULTS Along strands of smooth muscle in the CC and CS, rich numbers of VAChT-, nNOS-, VIP-, TH-, and very few HO-1-immunoreactive (-IR) nerve fibers were observed. Immunoreactivities for VAChT and nNOS, VAChT and VIP, and nNOS and VIP, were generally found in the same varicose nerve terminals. TH-IR nerve fibers or terminals did not contain immunoreactivities for VAChT, NOS or VIP. In the endothelium lining penile arteries, immunoreactivities for eNOS, HO-1, and HO-2 were detected. Single endothelial cells, lining the sinusoidal walls of the CC and CS, were found also to contain eNOS and HO-immunoreactivities. Noradrenaline (NA)-contracted preparations of CC and CS were relaxed by NO, CO, carbachol and by electrical stimulation of nerves. Inhibition of NO synthesis abolished electrically- and carbachol-induced relaxation. In NA-activated strips, relaxation induced by exogenously applied NO, but not those by CO, were accompanied by increases in intracellular levels of cyclic GMP. CONCLUSIONS VAChT, NOS and VIP are found in the same nerve terminals within the human CC and CS, suggesting that these terminals comprise a distinct population of parasympathetic, cholinergic nerves. Endothelially derived NO and the HO/CO system may have a complementary role in penile erection.
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Affiliation(s)
- P Hedlund
- Departments of Clinical Pharmacology and Pathology, Lund University Hospital, Sweden
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Hedlund P, Ny L, Alm P, Andersson KE. Cholinergic nerves in human corpus cavernosum and spongiosum contain nitric oxide synthase and heme oxygenase. J Urol 2000; 164:868-75. [PMID: 10953170 DOI: 10.1097/00005392-200009010-00064] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
PURPOSE To characterize the distribution of cholinergic nerves in the human corpus cavernosum (CC) and spongiosum (CS) using antibodies to the vesicular acetylcholine transporter (VAChT), and to compare this distribution to those of other transmitters/mediators or transmitter/mediator generating enzymes (heme oxygenases: HO-1 and HO-2; neuronal and endothelial NO synthases: nNOS and eNOS; vasoactive intestinal polypeptide: VIP; and tyrosine hydroxylase: TH), and to investigate NO- and carbon monoxide (CO)-mediated effects. MATERIALS AND METHODS Immunocytochemistry, confocal laser scanning microscopy, radioimmunoassay, and functional in vitro studies. RESULTS Along strands of smooth muscle in the CC and CS, rich numbers of VAChT-, nNOS-, VIP-, TH-, and very few HO-1-immunoreactive (-IR) nerve fibers were observed. Immunoreactivities for VAChT and nNOS, VAChT and VIP, and nNOS and VIP, were generally found in the same varicose nerve terminals. TH-IR nerve fibers or terminals did not contain immunoreactivities for VAChT, NOS or VIP. In the endothelium lining penile arteries, immunoreactivities for eNOS, HO-1, and HO-2 were detected. Single endothelial cells, lining the sinusoidal walls of the CC and CS, were found also to contain eNOS and HO-immunoreactivities. Noradrenaline (NA)-contracted preparations of CC and CS were relaxed by NO, CO, carbachol and by electrical stimulation of nerves. Inhibition of NO synthesis abolished electrically- and carbachol-induced relaxation. In NA-activated strips, relaxation induced by exogenously applied NO, but not those by CO, were accompanied by increases in intracellular levels of cyclic GMP. CONCLUSIONS VAChT, NOS and VIP are found in the same nerve terminals within the human CC and CS, suggesting that these terminals comprise a distinct population of parasympathetic, cholinergic nerves. Endothelially derived NO and the HO/CO system may have a complementary role in penile erection.
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Affiliation(s)
- P Hedlund
- Departments of Clinical Pharmacology and Pathology, Lund University Hospital, Sweden
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Cartledge JJ, Eardley I, Morrison JF. Impairment of corpus cavernosal smooth muscle relaxation by glycosylated human haemoglobin. BJU Int 2000; 85:735-41. [PMID: 10759676 DOI: 10.1046/j.1464-410x.2000.00599.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To examine the effect of HbA1c, an isoform of glycosylated haemoglobin (GHb, a product of non-enzymatic reactions between elevated blood glucose and haemoglobin), on nitric oxide-mediated corpus cavernosal smooth muscle relaxation, and to categorize the mechanisms involved. MATERIALS AND METHODS Corpus cavernosal tissue from Wistar rats (300-350 g body weight) was prepared for the measurement of isometric tension. After equilibration in Krebs solution gassed with 95% O2/5% CO2 at 37 degrees C for 90 min, optimal resting tension was applied. Tissue was precontracted with 1 micromol/L noradrenaline (NAd) and either relaxed with incremental doses of acetylcholine (ACh) or sodium nitroprusside (SNP). After washout, strips were again precontracted with NAd and then incubated with pyrogallol (100 micromol/L), 100 microL of haemoglobin or 100 microL of GHb in the presence of either L-arginine (100 micromol/L), indomethacin (10 micromol/L), allopurinol (100 micromol/L), deferoxamine (100 micromol/L), catalase (600 IU/mL), or superoxide dismutase (SOD) (120 IU/mL) before ACh- or SNP-induced relaxation responses were repeated. RESULTS Haemoglobin and GHb significantly impaired the relaxation of rat corpus cavernosum to ACh in a dose-dependent manner. L-arginine reversed the impairment caused by Hb, but not GHb. A donor of superoxide anions, pyrogallol, mimicked this impairment to ACh when added to control strips. Catalase, deferoxamine, indomethacin and allopurinol had no significant effect on the impaired relaxation response to ACh, whilst L-arginine partially reversed it. SOD completely reversed the GHb-induced impaired relaxation; GHb did not alter the relaxation response to SNP. CONCLUSION GHb significantly impairs endothelial NO-mediated corpus cavernosal relaxation in the rat, in vitro. This effect is caused partly by the generation of superoxide anions and the extracellular inactivation of NO.
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Affiliation(s)
- J J Cartledge
- Pyrah Department of Urology, St James's University Hospital, Leeds, UK.
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Escrig A, Marin R, Mas M. Repeated PGE1 treatment enhances nitric oxide and erection responses to nerve stimulation in the rat penis by upregulating constitutive NOS isoforms. J Urol 1999; 162:2205-10. [PMID: 10569620 DOI: 10.1016/s0022-5347(05)68160-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
PURPOSE To assess whether intracavernosal injections of prostaglandin E1 (PGE1) can influence nitric oxide (NO) release in the corpora in a rat model of penile erection. MATERIALS AND METHODS The extracellular levels of NO were monitored at 100 seconds intervals in the corpus cavernosum of anesthetized rats by using differential normal pulse voltammetry with porphyrin-Nafion coated carbon fiber microelectrodes. The intracavernosal pressure (ICP) was simultaneously recorded. PGE1 was given either as a single dose (ranging from 0.2 to 15 microg.) or as repeated 2 microg. injections in alternate days for two weeks. The NO and ICP responses to electrostimulation of the cavernosal nerve (SCN) was studied in the animals in the repeated treatment schedule at 1, 7, 15 and 30 days after its termination. The levels of the three NO synthase (NOS) isoforms in the cavernous tissue were measured by immunoblotting. RESULTS Acute PGE1 treatment dose-relatedly increased NO levels in the corpora, with a concomitant ICP increase with the highest dose. Repeated 2 microg. PGE1 injections increased the NO and ICP responses to SCN as compared with intact or vehicle-injected animals. This treatment also increased the penile content of the neuronal and endothelial NOS proteins. The inducible NOS isoform remained unchanged after either vehicle or PGE1 injections. The effects of the repeated PGE1 treatment were greater in the group studied 24 hours after the last injection and decreased progressively thereafter. CONCLUSIONS Stimulation of NO release can contribute to the erectogenic effect of intracavernous PGE1 injections. The increased levels of constitutive NOS isoforms in the corpora could contribute to the improvement of the erectile function reported by some patients following repeated treatment with vasorelaxant agents.
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Affiliation(s)
- A Escrig
- University of La Laguna, School of Medicine, Department of Physiology, Tenerife, Spain
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Marin R, Escrig A, Abreu P, Mas M. Androgen-dependent nitric oxide release in rat penis correlates with levels of constitutive nitric oxide synthase isoenzymes. Biol Reprod 1999; 61:1012-6. [PMID: 10491638 DOI: 10.1095/biolreprod61.4.1012] [Citation(s) in RCA: 77] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
Androgens are known to influence penile erection and nitric oxide synthase (NOS) activity in cavernosal tissue homogenates. The present study was an assessment of the effects of castration and androgen replacement on the in vivo release of nitric oxide (NO), and of the simultaneously recorded intracavernosal pressure (ICP) changes elicited by electrostimulation of the cavernosal nerves (SCN) in the anesthetized rat. The extracellular levels of NO in the corpora were monitored electrochemically using porphyrin microsensors. The content of NOS isoenzymes in corporal homogenates was determined by immunoblotting. The responses of castrated rats with or without testosterone (T) implants were compared to those of intact animals. Castration virtually abolished both the NO and the ICP responses to SCN. There was a concomitant significant decrease in the content of both the neuronal (nNOS) and the endothelial (eNOS) isoenzymes in the cavernosal tissue. All these effects of castration were prevented by T replacement. The NO response to SCN was positively correlated with the levels of nNOS and eNOS, especially when the values of the two isoforms were added (r = 0.71, P < 0.001). These data suggest that the facilitatory action of androgens on penile erection involves the up-regulation of both constitutive NOS isoenzymes in the corpora cavernosa.
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Affiliation(s)
- R Marin
- Department of Physiology, School of Medicine, University of La Laguna, 38071 Tenerife, Spain
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33
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Way KJ, Reid JJ. The effects of diabetes on nitric oxide-mediated responses in rat corpus cavernosum. Eur J Pharmacol 1999; 376:73-82. [PMID: 10440092 DOI: 10.1016/s0014-2999(99)00347-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Nitric oxide (NO)-mediated responses were investigated in corpora cavernosa isolated from 8-week diabetic rats. Relaxations to field stimulation were abolished by N(G)-nitro-L-arginine (NOARG, 100 microM). Responses to stimulation and sodium nitroprusside were reduced in tissues from diabetic rats compared to control rats, when data were expressed as g tension, but not when expressed as g/g tissue. The endothelium-dependent vasodilator, acetylcholine, failed to relax tissues. Stimulation-induced contractions were smaller in the diabetic group compared to the control group when data were expressed as g tension, but not g/g tissue. Contractions were enhanced by NOARG, and inhibited by acetylcholine (300 microM), by a similar degree in both groups. NOARG reduced the inhibitory effect of acetylcholine in tissues from control, but not diabetic rats. The results suggest diabetes caused a general impairment in responsiveness of rat corpus cavernosum, which may be a consequence of tissue weight change. A role for endothelium-dependent NO could not be identified; however, NO-mediated modulation of noradrenergic transmission by acetylcholine, may be defective in diabetes.
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Affiliation(s)
- K J Way
- Department of Medical Laboratory Science, RMIT University, Melbourne, Victoria, Australia
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Hedlund P, Alm P, Andersson KE. NO synthase in cholinergic nerves and NO-induced relaxation in the rat isolated corpus cavernosum. Br J Pharmacol 1999; 127:349-60. [PMID: 10385233 PMCID: PMC1566028 DOI: 10.1038/sj.bjp.0702556] [Citation(s) in RCA: 68] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/1998] [Revised: 02/09/1999] [Accepted: 02/23/1999] [Indexed: 12/17/2022] Open
Abstract
1. In the rat corpus cavernosum (CC), the distribution of immunoreactivity for neuronal and endothelial NO synthase (nNOS and eNOS), and the pattern of NOS-immunoreactive (-IR) nerves in relation to some other nerve populations, were investigated. Cholinergic nerves were specifically immunolabelled with antibodies to the vesicular acetylcholine transporter protein (VAChT). 2. In the smooth muscle septa surrounding the cavernous spaces, and around the central and helicine arteries, the numbers of PGP- and tyrosine hydroxylase (TH)-IR terminals were large, whereas neuropeptide Y (NPY)-, VAChT-, nNOS-, and vasoactive intestinal polypeptide (VIP)-IR terminals were found in few to moderate numbers. 3. Double immunolabelling revealed that VAChT- and nNOS-IR terminals, VAChT- and VIP-IR terminals, nNOS-IR and VIP-IR terminals, and TH- and NPY-IR terminals showed coinciding profiles, and co-existence was verified by confocal laser scanning microscopy. TH immunoreactivity was not found in VAChT-, nNOS-, or VIP-IR nerve fibres or terminals. 4. An isolated strip preparation of the rat CC was developed, and characterized. In this preparation, cumulative addition of NO to noradrenaline (NA)-contracted strips, produced concentration-dependent, rapid, and almost complete relaxations. Electrical field stimulation of endothelin-1-contracted preparations produced frequency-dependent responses: a contractile twitch followed by a fast relaxant response. After cessation of stimulation, there was a slow relaxant phase. Inhibition of NO synthesis, or blockade of guanylate cyclase, abolished the first relaxant phase, whereas the second relaxation was unaffected. 5. The results suggest that in the rat CC, nNOS, VAChT- and VIP-immunoreactivities can be found in the same parasympathetic cholinergic neurons. Inhibitory neurotransmission involves activation of the NO-system, and the release of other, as yet unknown, transmitters.
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Affiliation(s)
- Petter Hedlund
- Department of Clinical Pharmacology, Institute of Laboratory Medicine, University of Lund, Sweden
| | - Per Alm
- Department of Pathology, Institute of Laboratory Medecine, University of Lund, Sweden
| | - Karl-Erik Andersson
- Department of Clinical Pharmacology, Institute of Laboratory Medicine, University of Lund, Sweden
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35
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Yildirim S, Ayan S, Sarioglu Y, Gültekin Y, Bütüner C. The effects of long-term oral administration of L-arginine on the erectile response of rabbits with alloxan-induced diabetes. BJU Int 1999; 83:679-85. [PMID: 10233579 DOI: 10.1046/j.1464-410x.1999.00962.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To investigate the effects of the long-term oral administration of L-arginine on the impaired neurogenic and endothelium-dependent relaxation responses of corpus cavernosum smooth muscle from alloxan-induced diabetic rabbits. MATERIALS AND METHODS Thirty-two New Zealand white rabbits were used in four groups of eight each. In group 1, the rabbits received no treatment after the induction of diabetes with alloxan hydrochloride given intravenously; in group 2, L-arginine (1 mg/mL) was administered orally after the induction of diabetes; in group 3, 6 U/day of insulin was injected subcutaneously; group 4 was maintained with no treatment (as litter-mate controls) for 8 weeks. Thereafter, the rabbits were killed by exsanguination and the penis removed en bloc. The reactivity of corpus cavernosum strips from the penis was then assessed in organ chambers. RESULTS Relaxation and contraction responses of corpus cavernosum strips to sodium nitroprusside and potassium chloride, respectively, were similar in all groups. Relaxation responses of corpus cavernosum strips elicited by electrical field stimulation and carbachol from rabbits in group 1 were less than in controls; the responses to carbachol were not significantly impaired in group 2 and 3, whereas responses to electrical field stimulation were impaired in both groups when compared with the control group. CONCLUSION The impairment of endothelium-dependent and nerve-mediated relaxation by diabetes appears to involve an alteration in nitric oxide/cyclic GMP pathway. Administration of oral L-arginine increased endothelium-dependent relaxation, probably through activating nitric oxide synthase. Additionally, decreasing elevated blood glucose concentration and advanced glycosylation products by insulin treatment protected endothelium-dependent relaxation, whereas neither L-arginine nor insulin treatment restored impaired neurogenic relaxation.
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Affiliation(s)
- S Yildirim
- Department of Pharmacology, School of Medicine, Cumhuriyet University, Sivas, Turkey
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36
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Escrig A, Gonzalez-Mora JL, Mas M. Nitric oxide release in penile corpora cavernosa in a rat model of erection. J Physiol 1999; 516 ( Pt 1):261-9. [PMID: 10066939 PMCID: PMC2269210 DOI: 10.1111/j.1469-7793.1999.261aa.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
1. Nitric oxide (NO) levels were measured in the corpus cavernosum of urethane-anaesthetized rats by using differential normal pulse voltammetry with carbon fibre microelectrodes coated with a polymeric porphyrin and a cation exchanger (Nafion). A NO oxidation peak could be recorded at 650 mV vs. a Ag-AgCl reference electrode every 100 s. 2. This NO signal was greatly decreased by the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), given by local and systemic routes, and enhanced by the NO precursor L-arginine. Treatment with L-arginine reversed the effect of L-NAME on the NO peak. 3. Both the NO signal and the intracavernosal pressure (ICP) were increased by electrical stimulation of cavernosal nerves (ESCN). However, the rise in the NO levels long outlived the rapid return to baseline of the ICP values at the end of nerve stimulation. 4. The ICP and the NO responses to ESCN were suppressed by local and systemic injections of L-NAME. Subsequent treatment with L-arginine of L-NAME-treated animals restored the NO signal to basal levels and the NO response to ESCN. The ICP response to ESCN was restored only in part by L-arginine. 5. The observed temporal dissociation between the NO and ICP responses could be accounted for by several factors, including the buffering of NO by the blood filling the cavernosal spaces during erection. 6. These findings indicate that an increased production of NO in the corpora cavernosa is necessary but not sufficient for maintaining penile erection and suggest a complex modulation of the NO-cGMP-cavernosal smooth muscle relaxation cascade.
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Affiliation(s)
- A Escrig
- Department of Physiology, School of Medicine, University of La Laguna, 38071 Tenerife, Spain
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37
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Rajasekaran M, Mondal D, Agrawal K, Chen IL, Hellstrom W, Sikka S. Ex vivo expression of nitric oxide synthase isoforms (eNOS/iNOS) and calmodulin in human penile cavernosal cells. J Urol 1998; 160:2210-5. [PMID: 9817372 DOI: 10.1097/00005392-199812010-00088] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
PURPOSE Nitric oxide (NO) synthesized by nitric oxide synthase (NOS) is recognized as the central mediator of penile erection. This process appears to be mediated mainly by neuronal NOS (nNOS), which is localized to the nonadrenergic, noncholinergic innervation of the penis. However, the role of non-neuronal penile constituents (specifically the cavernosal smooth muscle), as well as other NOS isoforms in NO production in the human penis is not well understood. The present study evaluates the expression of non-neuronal (inducible and endothelial) isoforms of NOS in human penile cavernosal smooth muscle cells in culture. MATERIALS AND METHODS Primary culture was initiated with explants of human corpora cavernosa. For gene expression studies, total RNA was extracted from cavernosal cells and subjected to reverse transcriptase polymerase chain reaction (RT-PCR). For NADPH-diaphorase histochemistry, the cells were incubated with 1 mM beta-NADPH and 0.5 mM nitrobluetetrazolium at 37C for 3 hours. For indirect immunofluorescence and electron microscopy, cells were incubated overnight at 4C with specific primary (eNOS; calmodulin) and secondary antibodies. A conventional avidin biotin complex technique was used for electron microscopy. RESULTS The mRNA expression studies revealed that these cells express both endothelial (eNOS) and inducible (iNOS) forms. Localization studies showed positive signals for NADPH-diaphorase, eNOS, and calmodulin. The electron microscopic evaluation confirmed the localization of eNOS to the cytoplasm and small vesicles in the cells. CONCLUSIONS These findings support the hypothesis that human cavernosal smooth muscle cells express both endothelial and inducible forms of NOS, which may significantly contribute to NO production in the penile architecture during the erectile process.
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Affiliation(s)
- M Rajasekaran
- Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana 70112-2699, USA
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38
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EX VIVO EXPRESSION OF NITRIC OXIDE SYNTHASE ISOFORMS (eNOS/iNOS) AND CALMODULIN IN HUMAN PENILE CAVERNOSAL CELLS. J Urol 1998. [DOI: 10.1016/s0022-5347(01)62298-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Abstract
The present paper deals with the origin and neurochemical characteristics of autonomic postganglionic and sensory nerve fibres supplying the mammalian vas deferens. The vas deferens is innervated by postganglionic nerve fibres originating primarily from neurons in pelvic ganglia and, to a lesser extent, from neurons in the inferior mesenteric ganglion and sympathetic chain ganglia as well as by sensory nerve fibres arising from dorsal root ganglia. Three major populations of nerve terminals innervating the organ can be distinguished: (1) noradrenergic fibres; (2) cholinergic fibres containing vasoactive intestinal polypeptide, neuropeptide Y, nitric oxide synthase, and (in the pig) somatostatin, supplying particularly the lamina propria; and (3) non-noradrenergic, presumably sensory fibres, containing calcitonin gene-related peptide and/or substance P. The population of noradrenergic nerves is the most common. In the pig, it can be divided into three subpopulations: a somatostatin-containing, a Leu-enkephalin-containing and a subpopulation immunonegative to these peptides, in descending order of magnitude. In the rat, guinea-pig, and man, NPY seems to be the most common peptide occurring in the noradrenergic axons. In the pig, coexistence patterns of the substances existing within nerve fibres supplying the vas deferens blood vessels are clearly different from those found in nerve fibres innervating the organ wall. The majority of the noradrenergic fibres associated with blood vessels contain neuropeptide Y only, while non-noradrenergic perivascular nerves contain predominantly vasoactive intestinal polypeptide. The possibility of different sources of origin of the particular nerve fibre subpopulations supplying the mammalian vas deferens and its blood vessels is discussed.
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Affiliation(s)
- J Kaleczyc
- Department of Animal Anatomy, Faculty of Veterinary Medicine, University of Agriculture and Technology, Olsztyn-Kortowo, Poland.
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41
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Segarra G, Medina P, Domenech C, Martínez León JB, Vila JM, Aldasoro M, Lluch S. Neurogenic contraction and relaxation of human penile deep dorsal vein. Br J Pharmacol 1998; 124:788-94. [PMID: 9690872 PMCID: PMC1565440 DOI: 10.1038/sj.bjp.0701883] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
1. The aim of the present study was to characterize neurogenic and pharmacological responses of human penile deep dorsal vein and to determine whether the responses are mediated by nitric oxide from neural or endothelial origin. 2. Ring segments of human penile deep dorsal vein were obtained from 22 multiorgan donors during procurement of organs for transplantation. The rings were suspended in organ bath chambers for isometric recording of tension. We then studied the contractile and relaxant responses to electrical field stimulation and to vasoactive agents. 3. Electrical field stimulation (0.5-2 Hz) and noradrenaline (3 x 10(-10)-3 x 10(-5) M) caused frequency- and concentration-dependent contractions that were of greater magnitude in veins denuded of endothelium. The inhibitor of nitric oxide synthesis NG-nitro-L-arginine methyl ester hydrochloride (L-NAME, l0(-4) M) increased the adrenergic responses only in rings with endothelium. 4. In preparations contracted with noradrenaline in the presence of guanethidine (10(-6) M) and atropine (10(-6) M), electrical stimulation induced frequency-dependent relaxations. This neurogenic relaxation was prevented by L-NAME, methylene blue (3 x 10(-5) M) and tetrodotoxin (10(-6) M), but was unaffected by removal of endothelium. 5. Acetylcholine (10(-8)-3 x 10(-5) M) and substance P (3 x 10(-11) -3 x 10(-7) M) induced endothelium-dependent relaxations. In contrast, sodium nitroprusside (10(-9)-3 x 10(-5) M) and papaverine (10(-8) 3 x 10(-5) M) caused endothelium-independent relaxations. 6. The results provide functional evidence that the human penile deep dorsal vein is an active component of the penile vascular resistance through the release of nitric oxide from both neural and endothelial origin. Dysfunction in any of these sources of nitric oxide should be considered in some forms of impotence.
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Affiliation(s)
- G Segarra
- Department of Physiology, University of Valencia, Spain
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42
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Alm P, Ekström J, Larsson B, Tobin G, Andersson KE. Nitric oxide synthase immunoreactive nerves in rat and ferret salivary glands, and effects of denervation. THE HISTOCHEMICAL JOURNAL 1997; 29:669-76. [PMID: 9413740 DOI: 10.1023/a:1026452715555] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Nitric oxide has been implicated in mechanisms mediating nerve-evoked vasodilatory and secretory responses in salivary glands. In the present study, the occurrence and distribution of nitric oxide synthase (NOS)-immunoreactive nerves in ferret and rat salivary glands were investigated using immunocytochemistry with rabbit and sheep NOS antisera, and using NADPH-diaphorase enzyme histochemistry. In the parotid, submandibular and sublingual glands of the rat and the ferret, NOS-immunoreactive varicose terminals encircled acini and arteries of various sizes. In the ferret, collecting ducts were also supplied with NOS-immunoreactive fibres. In the rat, only the granular ducts of the submandibular gland were supplied with such fibres. The NOS-immunoreactive innervation of acinar cells was more abundant in the rat than in the ferret, whereas the opposite was true for the innervation of blood vessels. No NOS immunoreactivity was observed in the vascular endothelium. In both species, NOS-positive ganglionic cell bodies were found in the hilar regions of the submandibular and sublingual glands, whereas none could be detected in the parotid glands. NADPH-diaphorase reactivity had the same neuronal distribution as NOS immunoreactivity and, in addition, NADPH-diaphorase reactivity was expressed in ductal epithelium. Neither sympathetic denervation (by removal of the superior cervical ganglion) nor treatment with the sensory neurotoxin capsaicin reduced the NOS-immunoreactive innervation of the parotid gland. However, parasympathetic denervation (by cutting the auriculo-temporal nerve) caused an almost total disappearance of the NOS-immunoreactive innervation. The present findings provide a morphological background to the suggested role of nitric oxide in parasympathetic secretory and vascular responses of salivary glands.
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Affiliation(s)
- P Alm
- Department of Pathology, University of Lund, Sweden
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Andersson KE, Stief CG. Neurotransmission and the contraction and relaxation of penile erectile tissues. World J Urol 1997; 15:14-20. [PMID: 9066089 DOI: 10.1007/bf01275151] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
The balance between contractant and relaxant factors controls the smooth muscle of the corpus cavernosum and determines the functional state of the penis (detumescence and flaccidity versus tumescence and erection). Noradrenaline contracts both the corpus cavernosum and penile vessels, mainly via stimulation of alpha(1)-adrenoceptors. Recent investigations have demonstrated the presence of several subtypes of alpha 1-adrenoceptors (alpha(1A), alpha(1B), and alpha(1D)) in the human corpus cavernosum and also that the noradrenaline-induced contraction in this tissue is probably mediated by two or, possibly, three receptor subtypes. Even if much of the available in vitro information suggests that endothelins (ETs) may be of importance for mechanisms of detumescence and flaccidity, the role of the peptides in the control of penile smooth-muscle tone in vivo is unclear, as is the question as to whether they can contribute to erectile dysfunction. For further evaluation of the clinical importance of ETs in penile physiology and pathophysiology, clinical studies on ET-receptor antagonists would be of interest. Neurogenic nitric oxide (NO) has been considered the most important factor for relaxation of penile vessels and the corpus cavernosum, but recent studies in mice lacking neurogenic NO synthase (NOS) have shown these animals to have normal erections. This focuses interest on the role of endothelial NOS and on other agents released from nerves or endothelium. For the time being the most effective means of inducing penile erection in men involves the intracavernous administration of prostaglandin E1 (PGE1). PGE1 may act partly by increasing intracellular concentrations of cyclic adenosine monophosphate (cAMP). Recent results obtained with the adenylate cyclase stimulator forskolin suggest that penile smooth-muscle relaxation leading to penile erection can be achieved through the cAMP pathway. Thus, transmitters and agents acting through this second-messenger system may significantly contribute to relaxation of penile smooth muscle and to erection.
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Affiliation(s)
- K E Andersson
- Department of clinical Pharmacology, University Hospital of Lund, Sweden
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Vanhatalo S, Klinge E, Sjöstrand NO, Soinila S. Nitric oxide-synthesizing neurons originating at several different levels innervate rat penis. Neuroscience 1996; 75:891-9. [PMID: 8951882 DOI: 10.1016/0306-4522(96)00216-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
While the crucial role of neurally produced nitric oxide in mediating penile erection is well established, the understanding of the peripheral neuroanatomy of the nitric oxide-ergic pathways is still incomplete. This study was designed to elucidate further the distribution of nitric oxide synthase, and its relation to the distribution of neuropeptides and tyrosine hydroxylase in all penis-projecting neural pathways. A triple-labelling technique was employed, with the retrograde tracer Fluoro Gold combined with neuropeptide immunohistochemistry and nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase histochemistry, a marker of nitric oxide synthase. The presence within the penis of scattered nerve cell bodies exhibiting NADPH-diaphorase activity was revealed. Most (76%) of the penis-projecting neurons in the major pelvic ganglion exhibited NADPH-diaphorase activity and immunoreactivity to vasoactive intestinal peptide, while none of them contained tyrosine hydroxylase. Sympathetic paravertebral postganglionic neurons, in turn, contained tyrosine hydroxylase, but did not exhibit NADPH-diaphorase activity. In the afferent, sensory neurons projecting to the penis from the dorsal root ganglia, NADPH-diaphorase activity coexisted with immunoreactivity to both substance P (8%) and calcitonin gene-related peptide (26%). Preganglionic neurons originating in the spinal cord intermediolateral column at the thoracolumbar level T11-L3 terminated, not only in the major pelvic ganglion, but also within the penis. The majority (81%) of the penis-projecting neurons exhibited NADPH-diaphorase activity. The results indicate that the rat penis receives several different nitric oxide-ergic neural projections. It is therefore possible that nitric oxide affects penile erection at several neuronal levels.
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Affiliation(s)
- S Vanhatalo
- Department of Anatomy, University of Helsinki, Finland
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