Pathophysiology Of Erectile Dysfunction Research Articles

Increased erythrocyte aggregation in men with coronary artery disease and erectile dysfunction

We studied the association between erythrocyte aggregation (EA) and erectile dysfunction (ED) in men with coronary artery disease (CAD). Men with CAD documented by coronary angiography filled the Sexual Health Inventory for Males questionnaire to detect ED and assess its severity. EA was evaluated by filming slides of blood smear. Low percentage of slide field covered by erythrocytes represented increased EA. Overall, 133 men with CAD, mean ages 62.4+/-12.2 years, were included: 100 (75.2%) with ED and 33 (24.8%) without ED. EA was increased among men with ED compared with men without ED (percentage of slide field covered by erythrocytes 66.7+/-14.7 vs 73.1+/-14.5%; P=0.03). After adjustment for age, diabetes mellitus, hemoglobin and hematocrit levels, EA was associated with ED severity (r=0.18; P=0.038). We conclude that EA is increased in men with CAD and ED. This finding may be relevant to the pathophysiology of ED in men with CAD.

Oral therapy for erectile dysfunction: An overview

Over the past 20 years, treat ment options for erectile dysfunction (ED) have become more effective and, despite the effectiveness of intracavernous injections, vacuum devices, surgery and other treatments, there has been a trend toward the development of less-invasive modalities. Oral drugs have become the first-line therapeutic option for many men with ED. This review highlights the pathophysiology of ED, oral therapy for ED and new drug targets for the treatment of ED products available in the market for ED.

Proteomic Analysis of Penile Protein Alterations in a Rat Model of Cavernous Nerve Injury

Purpose: Cavernous nerve resection (CNR) in rats is a standard model of animal experiments on erectile dysfunction (ED) that occurs after radical prostatectomy (RP). Injured cavernous nerves after surgery can cause fibrosis and apoptosis that lead to penile structural changes that may be accompanied by alterations of protein expression. This study aimed to analyze the changes in protein after CNR in Wistar Kyoto rats. Materials and Methods: Using 8-week-old male Wistar Kyoto rats, sham and CNR operation under a microscope were performed. Two and 8 weeks after surgery, we applied 2-DE and MALDI-TOF/TOF (AB 4700) to identify differently expressed penile proteins after CNR. 2-DE gels were stained with silver nitrate and were analyzed with PDQuest. After in-gel digestion, peptide mass spectra were obtained by MALDI-TOF/TOF mass spectrometry in the positive ion reflector mode. The obtained data were screened with a rat database from both the NCBI and the Swiss-Prot/TrFMBL home page. Results: The proteins that were changed more than 1.5-fold compared with the sham group were annexin A4 and pyruvate kinase (PK). Annexin A4 was increased by 1.75-fold after 2 weeks, whereas PK was decreased by 4.16 after 8 weeks. These results were confirmed by immunohistochemistry. Conclusions: Annexin A4 in the CNR group was increased, which may be related to emiocytosis during apoptosis. The decrease in PK of the CNR group is assumed to be related to a decrease in efficacy during glycolysis. Further study will be needed to elucidate the molecular pathophysiology of ED after cavernous nerve injury. (Korean J Urol 2009;50:498-504) 󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏

Amino-Terminal Pro-C-Type Natriuretic Peptide is Associated with the Presence, Severity, and Duration of Vasculogenic Erectile Dysfunction

BackgroundEndothelial dysfunction is a key event in the pathophysiology of erectile dysfunction (ED) and generalized vascular disease. C-type natriuretic peptide (CNP) is a paracrine molecule that effects endothelial integrity and vascular tone. ObjectiveTo determine the role of CNP in men with vasculogenic ED. Design, setting, and participantsFifty-two consecutive men (age: 57±10 yr) with nonpsychogenic and nonhormonal ED for >6 mo and free of cardiovascular disease who were referred to the Cardiovascular Diseases and Sexual Health Unit of our Department for evaluation of ED were compared with 31 subjects with normal erectile function matched for age, body mass index, and traditional risk factors. MeasurementsVasculogenic ED was diagnosed according to comprehensive history, physical examination, Sexual Health Inventory for Men (SHIM-5) scoring, hormonal testing, and penile color-Doppler ultrasound. Amino-terminal proCNP (NT-proCNP) was measured in plasma with enzyme-linked immunosorbent assay (ELISA). Results and limitationsCompared to controls, ED patients had significantly lower NT-proCNP levels (0.21±0.08pmol/l in ED patients vs 0.34±0.07pmol/l in control subjects; p<0.001). NT-proCNP levels were associated with erectile performance as expressed by SHIM-5 score (r=0.57; p<0.001), even after adjusting for confounders. There was also an inverse linear relationship between ED duration and NT-proCNP levels (p<0.05). In patients with arteriogenic ED, there was a positive correlation of NT-proCNP levels with peak systolic velocity (PSV) (r=0.51; p=0.01). ConclusionsCNP levels are associated with the presence, severity, and duration of ED. These findings provide further insight into the role of CNP in the pathophysiology of ED.

Penile and Systemic Endothelial Function in Men with and without Erectile Dysfunction

BackgroundAssessment of endothelial function can provide essential information about the mechanisms of cardiovascular disease. Emerging data show that erectile dysfunction (ED) can precede the symptoms of ischemic heart disease, and this suggests that endothelial dysfunction is the link between these two clinical entities. ObjectiveTo evaluate penile and systemic endothelial function in subjects with and without ED. Design, setting, and participantsFifty-nine subjects were enrolled in the study. According to their International Index of Erectile Function (IIEF) ED domain scores, they were divided into two groups: 40 patients with ED and 19 men without ED (control group). Hemodynamic measurements, penile endothelial function, and forearm endothelial function were assessed in all participants using veno-occlusive plethysmography. MeasurementsWe measured baseline blood flow in both the forearm and the penis and calculated the corresponding vascular resistances. Postischemic changes in blood flow were recorded serially in both organs for the evaluation of endothelial function. Area under the flow-time curve (AUC), and maximal blood flow after ischemia were considered to be the indices of endothelial function. Results and limitationsGeneral characteristics of the two groups of participants were comparable except for age (40.5±3.3 yr in the control group vs 53.3±2.3 yr in the ED group). Baseline forearm blood flow was similar in the two groups, but the penile blood flow was significantly lower in men with ED compared with that in the men without ED: 6.2±0.6 versus 8.6±0.6ml/min per 100ml of tissue (p=0.006). Penile vascular resistance was higher in the ED group compared with the control group. The indices of forearm endothelial function were comparable in both groups (p=0.70 for the AUCs). However, indices of penile endothelial function were significantly higher in the control group compared with those of the ED group (AUC: 950 units±130 vs 450±80 units, p=0.001). ConclusionsThe use of veno-occlusive plethysmography for evaluating penile endothelial function is simple and reliable and provides new information on the pathophysiology of ED at the level of penile vasculature. This is the first study that provides evidence of impaired penile endothelial function without the presence of a significant peripheral endothelial dysfunction. Furthermore, these results provide further support for the notion that the development of ED could predict the future onset of cardiovascular disease.

ASSOCIATION STUDY OF ENDOTHELIAL NITRIC OXIDE SYNTHASE (NOS3) GENE POLYMORPHISMS AND SCHIZOPHRENIA

To investigate the effect of 2 endothelial nitric oxide synthase gene polymorphisms, namely, variable number of 27-bp tandem repeats in intron 4 and T-786C in the promoter region, on the susceptibility to erectile dysfunction (ED) in Turkish population.A total of 72 patients with ED (mean age 54.3 ± 9.2 years) diagnosed by Doppler ultrasonography and 71 healthy controls (mean age 55.4 ± 8.2 years) were analyzed. Genotypes were determined through polymerase chain reaction with or without restriction endonuclease digestions.Genotype distribution for CC genotype of T-786C polymorphism in promoter was significantly different between patients with ED and controls, the genotype frequency being 31.9% and 12.7%, respectively (P = .019). The univariate odds ratio (OR) associated with CC alleles revealed 3 times increased risk for ED (OR = 3.2; 95% confidence interval [CI], 1.4-7.6; P = .006). The risk also holds when excluding patients with hypertension and diabetes mellitus (P = .012, OR = 3.1; 95% CI, 1.2-7.7) as well as obesity (P = .05, OR = 4; 95% CI, 1.05-15.3). Patients with CC genotype of promoter present earlier symptoms of ED (51.7%) compared with controls (10.7%) (P <.001). No significant correlation was observed with variable number of tandem repeats in intron 4 and with the type of vascular insufficiency.The CC genotype of T-786C polymorphism in the promoter of eNOS gene is associated with increased risk of ED in Turkish population. Earlier onset of ED with CC genotype suggests that CC allele is an independent risk factor for endothelial dysfunction in the absence of other risk factors (hypertension, diabetes mellitus, obesity). An impaired NO production because of CC alleles may account for pathophysiology of ED.

Pharmacotherapy for erectile dysfunction

Objective: To review advances in the pharmacological treatment of erectile dysfunction (ED) highlighting potential neuro-endocrine and molecular targets. Methods: A comprehensive MEDLINE and PUBMED search was utilized to investigate current novel mechanistic approaches in treating erectile dysfunction. Search criteria included, but were not limited to, erectile dysfunction (ED), cGMP, nitric oxide, Rho-kinase, phosphodiesterase, gene therapy, apomorphine, melanocortin and corpora cavernosa. Articles relating to in vitro, animal and in vivo experimental therapy were evaluated and included in this review and future directions are described. Results: Current first-line ED treatment often involves the use of phosphodiesterase inhibitors. However, many novel pharmacotherapeutic approaches under development including the use of melanocortins and Rho-kinase inhibitors as well as the introduction of gene therapy have demonstrated efficacy in animal as well as early human trials. Conclusions: The success of oral pharmacotherapy for ED has been accompanied by renewed interest into the ED pathophysiology and signal transduction pathways. This has led to the identification of new therapeutic targets, which are poised to change the dynamic of ED management by broadening treatment alternatives to include other oral and genetic therapies.

A functional study of purinergic signalling in the normal and pathological rabbit corpus cavernosum

To examine rabbit cavernosal smooth muscle (CSM) relaxation to ATP, ADP and UTP in normal rabbits and in models of conditions that predispose to erectile dysfunction (ED), diabetes mellitus (DM; induced for 6 months) and bladder outlet obstruction (BOO, 6 weeks after surgery). Concentration-response curves (CRCs) were constructed to ATP, ADP and UTP on CSM from control rabbits in the absence and presence of antagonists. In addition, CRCs were constructed to ATP in CSM from rabbits with DM and BOO. ATP and UTP caused equipotent, dose-dependent relaxations of pre-contracted normal rabbit CSM; ADP was more potent. Relaxation was inhibited by Reactive Blue 2, but not by suramin, 8-p-sulfophenyltheophylline or L-N(G)-nitroarginine methyl ester. In rabbits with DM and those with partial BOO, ATP-mediated CSM relaxation was less than in control rabbits. Pharmacological profiling suggests that purine-induced CSM relaxation might be mediated by P2Y(1) and P2Y(4) receptors in the rabbit. In healthy rabbits, ATP released from nerves appears to produce relaxation of CSM via P2Y(4) receptors on smooth muscle, while ADP, acting on P2Y(1) receptors on endothelial cells, produces relaxation via nitric oxide. Alterations in CSM purinergic signalling might be implicated in the pathophysiology of ED associated with DM and BOO. Characterization of purinergic signalling in CSM might highlight new therapeutic targets for treating ED.

Growth factors for therapeutic angiogenesis in hypercholesterolemic erectile dysfunction

The past decade has seen an explosion of new information on the physiology of penile erection, and pathophysiology of erectile dysfunction (ED). Hypercholesterolemia is a chronic condition that can lead to degeneration in the vasculature bed and can result in ED if the penile vasculature is involved. Angiogenesis is the growth of new blood vessels from preexisting vasculature. Therapeutic angiogenesis seeks to harness the mechanisms of vascular growth to treat disorders of inadequate tissue perfusion, such as coronary artery disease and ED. There have been tremendous changes in the field of therapeutic angiogenesis over the past decade, and there is much promise for the future. Initial preclinical work with cytokine growth factor delivery resulted in a great deal of enthusiasm for the treatment of ischemic heart and/or peripheral vascular disease, though clinical studies have not achieved similar success. With an increased understanding of the complex mechanisms involved in angiogenesis, novel therapies which target multiple different angiogenic pathways are also being developed and tested. The penis is a convenient tissue target for gene therapy because of its external location and accessibility, the ubiquity of endothelial lined spaces, and low level of blood flow, especially in the flaccid state. Therapeutic angiogenesis is an exciting field that continues to evolve. This review will focus on the development of growth factors for hypercholesterolemic ED, the use of various growth factors for ED therapy, their routes of delivery, and the results in animal studies.

Chloroquine-induced nitric oxide as a potential treatment of erectile dysfunction associated with the metabolic syndrome: the science and the fiction

Erectile dysfunction is an important cause of decreased quality of life in men. It is estimated that ∼ 30 million men in the US and 100 million worldwide may have erectile dysfunction. Data from epidemiological studies indicate a higher prevalence of impotence in obese men. Obesity may be a risk factor for sexual dysfunction in both sexes; data for the metabolic syndrome are very preliminary and need to be confirmed in larger epidemiological studies. The high prevalence of erectile dysfunction in patients with cardiovascular risk factors suggests that abnormalities of the vasodilator system of penile arteries play an important role in the pathophysiology of erectile dysfunction. Nitric oxide released during non-adrenergic, non-cholinergic neurotransmission and from the endothelium is probably the principal neurotransmitter mediating penile erection. It has been shown that chloroquine administration was associated with an increase in nitric oxide synthesis. Chloroquine was also postulated to enhance insulin sensitivity, which suggests potential benefit in treating the metabolic syndrome-related erectile dysfunction.

Sexual Function in Chronic Kidney Disease

Endocrine abnormalities are common in patients with chronic kidney disease (CKD) and lead to sexual dysfunction, anemia, hyperparathyroidism, and altered mineral metabolism. Common clinical problems include disturbances in menstruation in women, erectile dysfunction in men, and decreased libido and infertility in both sexes. Organic factors tend to be prominent and are related to uremia and other comorbid illnesses. Psychological factors and depression may exacerbate the primary problem. Alterations in the hypothalamic-pituitary axis are seen early in CKD and tend to worsen after patients start dialysis. Hypogonadism plays a dominant role in male sexual function, whereas changes in hypothalamic-pituitary function predominate in female sexual dysfunction. In patients on dialysis, treatment strategies include optimizing dose of dialysis, correction of anemia with erythropoietin, and correction of hyperparathyroidism. Successful kidney transplantation may restore normal sexual function, especially in younger patients.

Sexual dysfunction and the Mediterranean diet

To discuss present knowledge about the relation between sexual dysfunction, metabolic factors and the Mediterranean-style diet. Review of the literature and personal perspectives. Sexual problems appear to be widespread in society, influenced by both health-related and psychosocial factors, and are associated with impaired quality of life. Epidemiological studies suggest that modifiable health behaviours, including physical activity and leanness, are associated with a reduced risk for erectile dysfunction (ED) among men. Data from other surveys also indicate a higher prevalence of impotence in obese men. Obesity and the metabolic syndrome may be a risk factor for ED. The high prevalence of ED in patients with cardiovascular risk factors suggests that abnormalities of the vasodilator system of penile arteries play an important role in the pathophysiology of ED. We have shown that one-third of obese men with ED can regain their sexual activity after 2 years of adopting health behaviours, including a Mediterranean-style diet associated with regular exercise. Western societies actually spend a huge part of their health care costs on chronic disease treatment and interventions for risk factors. The adoption of healthy lifestyles can reduce the prevalence of obesity and the metabolic syndrome, and hopefully the burden of sexual dysfunction.

Cardiovascular disease, metabolic syndrome and erectile dysfunction

Erectile dysfunction and cardiovascular disease share the same risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking, all of which are implicated in causing endothelial dysfunction. In this review, an overview is given on the role of endothelium in the pathophysiology of erectile dysfunction, cardiovascular disease, and the metabolic syndrome as well as the links between them. Current literature offers strong evidence that endothelial dysfunction and erectile dysfunction are linked. Erectile dysfunction appears to be one of the earliest signs of systemic vascular disease and might be considered as an early marker for subclinical cardiovascular disease. Obesity is one of the many risk factors for cardiovascular disease and is also associated with hypertension, dyslipidemia, glucose intolerance, and insulin resistance, which together define the metabolic syndrome. Experimental, clinical, and epidemiologic studies support the association between metabolic syndrome and cardiovascular disease. The above-mentioned risk factors are a potential threat to the penile endothelium and the smooth muscle tissue leading to functional and structural changes. These important pathophysiologic factors are the foundation for the strong link between erectile dysfunction and cardiovascular disease. Recent literature supports the link between metabolic syndrome and erectile dysfunction and highlights metabolic syndrome as a potential risk factor for the development of erectile dysfunction.

Diabetic erectile dysfunction - an indicator of generalised endothelial function per se?

Erectile dysfunction (ED) affects up to 70% of men with diabetes. However, the pathophysiology of ED in diabetes remains uncertain with both neuronal and vascular factors cited. We examined whether ED is an indicator of generalized endothelial dysfunction. A unique group of diabetic patients free from established conventional cardiac risk factors were investigated. Forearm bloodflow responses to nitroprusside and acetylcholine on 11 diabetic men with ED and 11 potent diabetic men were measured by venous plethysmography. Patient characteristics between the impotent and potent patients were similar except for Hba1c which was higher in the group with ED (8.35% vs. 7.03%: p = 0.003). Both groups showed increases in FBF to incremental infusions of nitroprusside and acetylcholine but the area under curve (AUC) were similar in the ED and the non-ED groups (p = 0.16 and p = 0.17, respectively). We demonstrated that ED in patients with type 2 diabetes is not associated with additional generalized endothelial dysfunction.

Phosphodiesterase 5 Inhibitors in the Treatment of Erectile Dysfunction

Erectile dysfunction (ED) has multifactor pathogenesis, with neurological, vascular, endocrinological and psychogenic components described. However, about 50-85% of ED population report the presence of one or more comorbidities i.e. hypertension, diabetes, cardiovascular disease, dyslipidemia which all impair endothelial function and, erection is a basically vascular event that necessitates an intact endothelium to occur. Hence, ED may be mostly considered as the clinical manifestation of a disease affecting penile circulation as a part of a generalized vascular disorder due to atherosclerosis. Orally active drugs, i.e. phosphodiesterase type-5 inhibitors (PDE5-i), are a group of on-demand drugs licensed for ED treatment and appear to offer advantages over past therapies in terms of ease of administration and cost, and they are now widely advocated as first-line therapy. The recent discovery that chronic not on-demand administration of these drugs may improve erectile and endothelial response in men previously unresponding to on-demand regimes, opens a new scenario in the treatment of men with ED and comorbidities. Finally, the recent approval of PDE5-i sildenafil for the treatment of pulmonary arterial hypertension represents the new challenge for these class of drugs. Aim of this article will be to provide an update on the pathophysiology of ED and how to use of different available PDE5-i in approaching sexual dysfunctional men, pointing out on their characteristic of efficacy and safety and different indications in special sub-populations.

Existing and future pharmacotherapy for erectile dysfunction

Erectile dysfunction (ED) is a highly prevalent healthcare problem. For many decades treatment options were limited to either ineffective or invasive ones. The introduction of orally administered phosphodiesterase 5 (PDE5) inhibitors in clinical practice has been a revolution, offering patients and clinicians a well-tolerated, effective treatment. Despite their advantages, PDE5 inhibitors remain a symptomatic, on-demand treatment to which a number of patients fail to respond. Accumulated knowledge on ED pathophysiology and, particularly, on the importance of molecular pathways involved in erectile function has offered multiple targets for development of new therapies, intending not only to effectively treat symptoms, but also to correct the underlying abnormalities, thus giving hope for long-term remission or even cure of ED. The existing and future pharmacotherapy for ED will be reviewed in this article.

The evolving role of testosterone in the treatment of erectile dysfunction

Hypogonadism may play a significant role in the pathophysiology of erectile dysfunction (ED). A threshold level of testosterone may be necessary for normal erectile function. Testosterone replacement therapy is indicated in hypogonadal patients and is beneficial in patients with ED and hypogonadism. Monotherapy with testosterone for ED is of limited effectiveness and may be most promising in young patients with hypogonadism and without vascular risk factors for ED. A number of laboratory and human studies have shown the combination of testosterone and other ED treatments, such as phosphodiesterase type 5 (PDE5) inhibitors, to be beneficial in patients with ED and hypogonadism, who fail PDE5 inhibitor therapy alone. There is increasing evidence that combination therapy is effective in treating the symptoms of ED in patients for whom treatment failed with testosterone or PDE5 inhibitors alone. Testosterone replacement therapy has potentially evolved from a monotherapy for ED in cases of low testosterone, to a combination therapy with PDE5 inhibitors. Screening for hypogonadism may be useful in men with ED who fail prior PDE5 inhibitors, especially in populations at risk for hypogonadism such as type 2 diabetes and the metabolic syndrome.

The role of endothelial dysfunction in the pathophysiology of erectile dysfunction in diabetes and in determining response to treatment

Erectile dysfunction (ED) in diabetes is related to autonomic neuropathy and endothelial dysfunction. We studied the relative importance of these factors in diabetic and non-diabetic men with ED and determined if they predict responses to treatment with sildenafil. Thirty-three men, aged 35-65 years, with ED (20 diabetic, 13 non-diabetic), 15 of whom were sildenafil responders and 18 non-responders, were compared with 30 age and risk-matched control subjects (15 diabetic, 15 non-diabetic). Subjects with ED completed the International Index of Erectile Function (IIEF) questionnaire. Endothelial function was assessed by changes in brachio-radial and femoro-tibial arterial pulse-wave velocity (pulse-wave velocity) during reactive hyperaemia, expressed as percentage endothelium-dependent dilatation. Autonomic function was assessed by heart rate variation during expiration and inspiration (E/I ratio) and during the valsalva manoeuvre. The respective changes in pulse-wave velocity, in the arm and leg [mean (sd)] were 0.71 (6.5)% and 3.5 (6.4)% in the impotent diabetic men, 0.7 (7.6)% and 2.4 (5.9)% in the non-diabetic impotent men, -0.68 (5.7)% and -1.31 (7.2)% in the non-impotent diabetic men and 7.7 (3.7)% and 7.6 (3.4)% in the control subjects. There was a significant interaction between ED and diabetic status such that there was significantly impaired vascular response in the diabetic group (both with and without ED) and in the non-diabetic group with ED compared with the non-diabetic control group (P = 0.01 and P = 0.001 for brachio-radial and femoro-tibial measures, respectively). The E/I ratios of the diabetic men were significantly lower than those of the control subjects [1.17 (0.14) vs. 1.33 (0.16), P < 0.02), but there were no differences in the measures of autonomic neuropathy between the groups with ED and those with normal erectile function. Amongst diabetic men, the initial IIEF scores (maximum score 30, low score indicates more severe ED) were significantly higher in sildenafil-responders than non-responders [16.3 (8.4), vs. 6.8 (7 1), P < 0.02]. The rate of sildenafil response was not significantly affected by the measures of endothelial or autonomic function. ED in both diabetic and non-diabetic men is characterized by marked endothelial dysfunction in comparison with non-diabetic control subjects. Response to sildenafil is not predicted by either endothelial function or autonomic function, but in diabetic men appears to be related to the initial degree of erectile dysfunction.

Erectile dysfunction and coronary atherothrombosis in diabetic patients: pathophysiology, clinical features and treatment

The current review reports recent data available in the literature on the prevalence of erectile dysfunction and the association of erectile dysfunction with overt and silent coronary artery disease in patients with diabetes mellitus. The mechanisms by which erectile dysfunction is associated with coronary artery disease and potential clinical implications of this association have been extensively analysed. In particular, the role of endothelial dysfunction in the pathophysiology of erectile dysfunction and the potential clinical usefulness of erectile dysfunction to identify diabetic patients with silent coronary artery disease have been outlined. Finally, recent guidelines on the treatment of erectile dysfunction with phosphodiesterase-5 inhibitors in diabetic patients with and without coronary artery disease have been reported and discussed.

ENOS Function and Dysfunction in the Penis

Endothelial nitric oxide (NO) synthase (eNOS) has an indispensable role in the erectile response. In the penis, eNOS activity and endothelial NO bioavailability are regulated by multiple post-translational molecular mechanisms, such as eNOS phosphorylation, eNOS interaction with regulatory proteins and contractile pathways, and actions of reactive oxygen species (ROS). These mechanisms regulate eNOS-mediated responses under physiologic circumstances and provide various mechanisms whereby endothelial NO availability may be altered in states of vasculogenic erectile dysfunction (ED). In view of the recent advances in the field of eNOS function in the penis and its role in penile erection, the emphasis in this review is placed on the mechanisms regulating eNOS activity and its interaction with the RhoA/Rho-kinase pathway in the physiology of penile erection and the pathophysiology of ED.