Review

Correspondence *Royal Perth Hospital, GPO Box X2213, Perth, WA 6847, Australia

Email gerald.watts@uwa.edu.au

Introduction

Erectile dysfunction (ED) is the consistent inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance.¹ Vascular disease is by far the most common cause of ED. Formerly dismissed as a psychological condition, ED has now assumed center stage as a readily treatable disorder and a powerful risk-marker for cardiovascular disease (CVD).^{2, 3}

Here, we review the current knowledge of the pathogenesis of vasculogenic ED, with specific reference to abnormalities in the biology of nitric oxide (NO) and the relationship between and the clinical management of ED and CVD. Psychological and neurological aspects of ED have been reviewed elsewhere previously.²

Penile erection: central and peripheral mechanisms

The unique anatomy of the human penis is customized for producing a complex hemodynamic response to centrally and peripherally generated psychoneurogenic sexual stimuli. The effective evaluation and application of phosphodiesterase 5 (PDE5) inhibition in the management of ED has significantly elucidated the pathophysiological interrelationship between erectile and generalized endothelial dysfunction, and hence CVD.⁴

Central control of erectile function resides in the hippocampus and the medial preoptic area and paraventricular nuclei of the hypothalamus.⁵ The signaling of sexual impulses is mediated via the dopaminergic, nitrergic and oxytocinergic pathways, and is enhanced by bioavailable testosterone.^{5, 6} An erection is a coordinated process involving psychoneurogenic stimulation, arterial and cavernosal vasodilatation, increased blood flow and venous occlusion.

Peripheral control of erectile function centers on the interplay between relaxation and contraction of smooth muscle (SM) in the walls of the cavernosal arterioles and the trabeculae of the cavernosal sinuses. Vasodilatation caused by SM relaxation results in increased blood flow, increased intracavernosal pressure and occlusion of the subtunical venous plexus and emissary veins, leading to penile erection. SM cell relaxation is achieved through the cyclic GMP and cyclic AMP pathways, both of which are modulated by various chemomediators (Figure 1).

Figure 1 The physiology of penile erection—peripheral mechanisms

Chemomediators such as nitric oxide and endothelin translate effector signals from neuronal impulses into smooth muscle cell relaxation (erection) or smooth muscle contraction (detumescence). Abbreviations: cGMP, cyclic GMP; eNOS, endothelial nitric oxide synthase; nNOS, neuronal nitric oxide synthase; PDE5 phosphodiesterase type 5.

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NO, the principal chemomediator, is synthesized and released at the endings of nonadrenergic noncholinergic (NANC) parasympathetic nerves and by the vascular and sinusoidal endothelial cells, inducing SM relaxation.⁷ Noradrenaline and other sympathomimetic agents, on the other hand, cause SM contraction and vasoconstriction, hence penile detumescence and flaccidity.⁵ Other endothelial-derived molecules that help regulate penile blood flow include prostaglandins, bradykinin, hyperpolarizing factor, endothelin and angiotensin.^{8, 9} The physiology of the NANC parasympathetic nerve terminals and SM and endothelial cells of the cavernosal arterioles and trabeculae is pivotal to the peripheral mechanism of erectile function. Endothelial and neuronal dysfunction are, therefore, critical in the pathogenesis of ED.⁷

The role of nitric oxide in penile erection

Penile tumescence and erection is critically reliant on the release of NO by both cavernosal nerve terminals and endothelial cells.^{8, 9} NO activates guanylyl cyclase in penile SM cells, thereby converting GTP to cyclic GMP, with subsequent activation of protein kinase G and accelerated efflux of calcium and potassium from SM cells, ultimately increasing penile blood flow (Figure 1). The synthesis and release of NO by neuronal NO synthase (nNOS) in the cavernosal NANC nerve terminals is calcium-dependent and responsible for the initiation of penile erection following sexual stimulation.^{10, 11} Penile engorgement and shear stress activate a phosphoinositide 3 kinase/Akt signaling pathway, leading to further NO release by endothelial NO synthase (eNOS), which maintains the erection.¹⁰ These mechanisms are part of a feed-forward system (Figure 2). A defect in this system results in ED. The role of the endothelial cells in the maintenance of penile erection underscores the close association of ED with endothelial dysfunction in the peripheral circulation,¹² and with the presence of cardiovascular risk factors¹³ and coronary artery disease.³ Although we acknowledge that nNOS initiates penile erection and is involved in the neurogenic causes of ED, here we focus on the role of eNOS as the link between vasculogenic ED and cardiovascular risk.

Figure 2 The roles of two forms of nitric oxide synthase in cavernosal smooth muscle relaxation and the initiation and maintenance of penile erection

Abbreviations: Akt, protein kinase B; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; nNOS, neuronal nitric oxide synthase; P, phosphorylated; PI3K, phosphoinositide 3 kinase. Permission obtained from National Academy of Sciences © Hurt KJ et al. (2002) Proc Natl Acad Sci USA 99: 4061–4066.

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Endothelial dysfunction: beyond the corpus cavernosum

Endothelial dysfunction is intimately linked to atherogenesis and increased CVD risk.¹⁴ Dysfunction arises following alteration in the release of several vasoactive factors, principally NO, from endothelial cells.^{14, 15} NO is formed from L-arginine and molecular oxygen by eNOS, a reaction that in endothelial cells is triggered by a G-protein-coupled signaling pathway activated by shear stress or circulating bioactive agents, such as acetylcholine and 5-hydroxytryptamine. NO is released both subluminally, where it has vasodilatory and antiproliferative properties,¹⁵ and abluminally, where it exerts anticoagulant, antiadhesive and antiplatelet effects.

Endothelial dysfunction due to an abnormality in the release and/or action of NO is characterized by vasoconstriction, coagulation, increased leucocyte adhesion and stimulation of SM cell growth, and is, therefore, central to atherogenesis.¹⁴ Several traditional cardiovascular risk factors, such as aging, smoking, hypertension, dyslipidemia and diabetes, and some less-traditional risk factors, including inflammation, hypoxia, oxidative stress and homocysteinemia, are related to endothelial dysfunction.^{16, 17} It is also a feature of acute coronary syndromes, heart failure, reperfusion injury, renal failure, systemic inflammatory disorders and ED.^{14, 17}

Endothelial dysfunction can be tested in vivo using several techniques that rely principally on measuring change in arterial diameter or flow in response to stimuli, such as acetylcholine, 5-hydroxytryptamine or L-arginine, which increase the endothelial release and action of NO.¹⁸ Circulating biomarkers, such as high-sensitivity C-reactive protein (hsCRP), P-selectin, adhesion molecules and endothelial progenitor cells, have also been employed to assess endothelial dysfunction in clinical studies.¹⁸ Longitudinal observations confirmed that dysfunction of the endothelium of the coronary and peripheral circulation is predictive of cardiovascular events, the sensitivity and specificity being greater for coronary artery endothelial dysfunction than for peripheral dysfunction.¹⁹ Impaired NO-mediated vasodilatation of forearm resistance arteries reflects decreased total-body production of NO, supporting the link with ED.²⁰

The mechanism underlying endothelial dysfunction induced by cardiovascular risk factors, such as diabetes, hypertension, smoking and dyslipidemia, involves two processes: the inhibition of dimethylarginine dimethylaminohydrolase, which catalyses the hydrolysis of asymmetric dimethyl arginine, an inhibitor of eNOS; and the uncoupling of eNOS activity. Both processes increase oxidative stress in the endothelial cells.^{21, 22} This increase in oxidative stress leads to further oxidative catabolism of NO, formation of peroxynitrite, and activation of the proinflammatory nuclear factor kappa B, which in turn induces cellular inflammation and adhesion molecule production.^{15, 21} These mechanisms, and reduction in bone-marrow-derived endothelial progenitor cells, could underpin a common pathogenesis for both erectile and endothelial dysfunction.^{23, 24} In individuals with established ED, elevated asymmetric dimethyl arginine level has been shown to correlate with the severity of various cardiovascular risk factors, indicating the impact they could have on endothelial function.²⁵

Clinical assessment of erectile dysfunction

A patient with ED provides a unique clinical opportunity to detect cardiovascular risk factors and disease. Comprehensive investigation of medical, social and sexual history should be undertaken routinely, in addition to a physical examination and relevant laboratory and ancillary investigations. Initially, testing should include arterial blood pressure, waist circumference, fasting plasma lipids, glucose, glycated hemoglobin (HbA_1C), renal biochemistry, testosterone, hsCRP and resting 12-lead electrocardiography. Standard criteria should be used to identify the metabolic syndrome.²⁶

Although the diagnosis of ED per se relies heavily on the patient's perception and description of the problem, confirmation and assessment of its severity should be conducted with the internationally validated 5-item International Index of Erectile Function (IIEF-5) or the erectile function section of the 15-item IIEF.^{27, 28} The IIEF-5 (also known as the Sexual Health Inventory for Men [SHIM]) has been the preferred investigational instrument in ED studies. ED and various grades of ED severity, indicated by IIEF-5 scores, correlate significantly with CVD risk factors such as hypertension, diabetes, hyperlipidemia and obesity.^{29, 30, 31} Although not specifically reflective of nNOS and eNOS activity, question 3 of the Sexual Encounter Profile ("Did your erection last long enough for you to have successful intercourse?") and questions 3 ("How often were you able to maintain your erection after you had penetrated your partner?") and 4 ("How difficult was it to maintain your erection to completion of intercourse?") of the IIEF-5 are indicative of maintenance of erectile function. They could, therefore, be useful in identifying ED as a clinical manifestation of endothelial dysfunction.

The presence of significant psychogenic factors in the etiology of ED can be confirmed by the presence of adequate nocturnal penile tumescence. Duplex ultrasonographic imaging of the corpora cavernosa, dynamic infusion cavernosometry and cavernosography, and pharmacological stimuli can yield hemodynamic data that support a vasculogenic cause of ED.

Erectile dysfunction and cardiovascular risk

Several epidemiological studies in selected patient populations have clearly shown that the major cardiovascular risk factors—aging, smoking, diabetes, hyperlipidemia and hypertension—have raised prevalence in individuals with ED.^{13, 32} The prevalence of ED is also directly related to the number of cardiovascular risk factors present, being highest in individuals with more than three. Patients with coronary artery disease have a high frequency of ED,^{33, 34} which correlates with the number of stenotic and calcified arteries and predates symptomatic disease.^{35, 36, 37} Notably, a patient with vasculogenic ED is likely to have one coronary artery with a 50% stenosis.^{33, 34, 38}

Cardiometabolic risk in abdominally obese subjects is now well-defined by the metabolic syndrome rubric.²⁶ ED prevalence increases with the number of components of the metabolic syndrome, being as high as 40% in individuals with four components, and is especially prevalent in those with diabetes (Figure 3).³⁹ In individuals with the metabolic syndrome, ED has a linear relationship with evidence of endothelial dysfunction, as reflected by increased circulating plasma levels of hsCRP.⁴⁰ Obstructive sleep apnea, a feature of the metabolic syndrome, can also contribute to both endothelial and ED via several mechanisms, including hypoxia, hypogonadism and hyperadrenergic activity.^{41, 42} De Angelis et al. showed that in patients with type 2 diabetes and ED, the response of blood pressure to and degree of platelet aggregation following L-arginine administration—a surrogate test for endothelial dysfunction—is impaired when compared with those with type 2 diabetes and no ED.⁴³ In this analysis, the independent predictors of ED were HbA_1C, blood pressure response to l-arginine, circulating P-selectin levels and autonomic neuropathy. ED development in those with type 2 diabetes is principally related to both vasculopathy and neuropathy.^{2, 9}

Figure 3 The prevalence of erectile dysfunction, estimated by the IIEF-5 score, and serum high-sensitivity CRP levels in relation to components of the metabolic syndrome, as defined by the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults

Abbreviations: CRP, C-reactive protein; IIEF-5, 5-item International Index of Erectile Function. Permission obtained from American Diabetes Association © Esposito K et al. (2005) Diabetes Care 28: 1201–1203.

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A plausible theoretical link between erectile and endothelial dysfunction posits that cardiovascular risk factors could induce ED by impairing NO release from endothelial cells following neuronal activation and initiation of a penile erection. A residual, important question, however, is whether ED reflects endothelial dysfunction independent of traditional cardiovascular risk factors.

Erectile dysfunction: predictor of cardiovascular risk?

That CVD and its associated risk factors predict ED is now well accepted.³ New observational data, however, indicate that ED may independently predict CVD.^{44, 45, 46} Data from the placebo group of a large clinical trial indicate that prevalent or incident ED predicted the occurrence of cardiovascular events over a follow-up period of 9 years, with a hazard ratio of 1.45.⁴⁴ This association was independent of conventional cardiovascular risk factors, including age, hypertension, diabetes, hyperlipidemia and smoking. Over 5 years the incidence of ED was 57% and its presence predicted subsequent cardiovascular events to a degree either equal to or greater than that of cigarette smoking, hyperlipidemia or family history of myocardial infarction. These data are consistent with smaller studies showing that ED predates the development of symptomatic coronary disease.³⁶

In a cross-sectional study of patients with type 2 diabetes, analysis showed that ED, assessed by questionnaire, was the most-significant independent predictor of silent coronary artery disease (defined by angiography or stress testing) compared with other parameters, such as smoking, HbA_1c, microalbuminuria, hypertension and dyslipidemia.⁴⁷ In other studies, ED also independently correlated with coronary artery calcification³⁷ and left ventricular diastolic dysfunction.⁴⁵

In a case–control study, younger men with vasculogenic ED and no traditional cardiovascular risk factors or clinical CVD were shown to have impaired endothelium-dependent and endothelium-independent vasodilatation of the brachial artery⁴⁸—also an indicator for SM cell dysfunction in the peripheral circulation. An independent association between erectile and endothelial dysfunction, including increased plasma levels of endothelin-1 and adhesion molecules, and a reduction in circulating endothelial progenitor cells, has been confirmed by others.^{24, 46, 49} Our studies have shown an independent association between erectile and endothelial dysfunction, particularly in the resistance arteries, as demonstrated by impaired forearm plethysmography and increased pulse pressure in men with ED.⁵⁰ There is a possibility, however, that unmeasured risk factors, such as homocysteine level, insulin resistance and oxidative stress, could provide the missing link between erectile and endothelial dysfunction.¹⁷

While conclusive evidence is lacking, preliminary studies indicate that ED is a significant independent predictor of coronary events. Given that endothelial dysfunction predates atherosclerosis development, this possibility is consistent with the so-called 'artery size' hypothesis (Figure 4). This theory posits that atherogenesis is likely to present earlier with clinical symptoms in arteries of a smaller diameter, such as in the penis, than in larger sized arteries, such as in the coronary circulation.⁵¹ This hypothesis could be extended to the symptomatic manifestations of endothelial dysfunction in different arterial beds.

Figure 4 The 'artery size' hypothesis

This theory posits that luminal narrowing due to atherogenesis will manifest clinically earlier (A) in penile arteries (as erectile dysfunction), for example, than in (B) coronary arteries (as angina pectoris). Abbreviation: TIA, transient ischemic attack. Permission obtained from Elsevier Ltd © Montorsi P et al. (2005) Am J Cardiol 96 (Suppl): 19M–23M.

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Reversal of endothelial and erectile dysfunction

Two key questions need to be asked. First, can therapies proven to improve endothelial function and reduce cardiovascular risk improve ED? Second, can agents used to treat ED improve cardiovascular outcomes?

Several treatments improve endothelial dysfunction. Lifestyle changes, vitamin and food supplements, and a wide spectrum of pharmacotherapies can improve endothelium-dependent vasodilatation of the peripheral circulation in patients at risk of CVD, including those with multiple risk factors, insulin resistance and type 2 diabetes.^{52, 53} Some but not all of these therapies can also improve ED.

Lifestyle modification

In a 2-year randomized controlled trial, a weight loss and exercise program improved ED in 30% of obese male participants compared with nonobese controls.⁵⁴ Reversal of ED was paralleled by improvement in inflammatory marker levels, such as interleukin 6 (IL-6), and endothelial function, as estimated by the response of blood pressure and platelet aggregation following intravenously administered L-arginine. Lifestyle changes can, therefore, not only improve endothelial function and cardiovascular risk but also ED.^{54, 55} Notably, continuous positive air pressure can improve ED in obese patients with severe obstructive sleep apnea.⁵⁶

Cardiovascular drugs

Statins, fibrates and glitazones might have divergent effects on erectile and endothelial dysfunction. Several case reports and one lipid-clinic-based study have implicated statins and particularly fibrates in ED development.^{57, 58} Reports of recovery after drug withdrawal have varied. A recent prospective study has indicated that statins are more likely to induce ED in individuals with multiple cardiovascular risk factors and established endothelial dysfunction than in those at lower risk of CVD.⁵⁹ Whether this effect is neurogenic and related to statin lipophilicity is unclear. Only one large statin trial reported ED as an adverse event, although data were based on self-reporting and not IIEF scores.^{57, 60} A small study, however, has shown improved erectile function in men treated with the combination of atorvastatin and the PDE5 inhibitor sildenafil compared with sildenafil alone.⁶¹

Although a possible protective role of angiotensin-converting-enzyme (ACE) inhibition in ED was not confirmed in a recent placebo-controlled trial,⁶² a prospective study has indicated that combined ACE inhibitor and angiotensin-II-receptor antagonist therapy could benefit ED in patients at high risk of CVD.⁵⁹ Use of nonselective -adrenergic blockers, however, could be a reason for ED in patients with hypertension.⁶³ Valsartan can improve, whereas carvedilol can aggravate ED in newly diagnosed patients with hypertension.⁶⁴ There is clearly a need for further investigation, especially appropriately designed studies of erectile function with newer antihypertensive therapies, which are known to have a beneficial effect on endothelial function.

Phosphodiesterase type 5 inhibitors

The development and clinical introduction of PDE5 inhibitors has revolutionized the management of patients with ED. By inhibiting PDE5, these agents enhance the bioeffectiveness of NO in SM cells by increasing signaling from cGMP to protein kinase G, and hence the maintenance of penile blood flow (Figure 5).⁶⁵ Preclinical studies in healthy individuals showed that the PDE5 inhibitor sildenafil had a mild hypotensive effect and also improved arterial stiffness.⁶⁶ Several studies have now shown that PDE5 inhibitors improve coronary endothelial function in patients with ischemic heart disease and heart failure.^{67, 68}

Figure 5 Mechanism of action of phosphodiesterase type 5 inhibitors in inducing smooth-muscle relaxation in cavernosal arteries and in the peripheral circulation

Abbreviations: cGMP, cyclic GMP; PDE5, phosphodiesterase type 5.

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The benefits of treating pulmonary hypertension by enhancing the NO pathway in the local vasculature with sildenafil have also been identified, but the efficacy of this treatment remains to be confirmed in controlled clinical trials.⁶⁹ More recently, controlled observations have clearly shown that both sildenafil and the longer-acting tadalafil improve brachial artery flow-mediated dilatation in men at increased risk of CVD, including those with type 2 diabetes.^{70, 71} Improvements have also been reported in patients with type 2 diabetes within 1 h of 25 mg sildenafil being administered orally, with sustained improvement after continuing therapy for 4 weeks.⁷⁰ Similarly, significant improvements in endothelial function in the brachial artery remained 2 weeks after stopping tadalafil in men at increased risk of CVD.⁷¹ This finding was corroborated by increased plasma concentration of NO and reduced endothelin-1 levels.⁷¹ A recent study has also indicated there could be an interactive benefit from adding a PDE5 inhibitor to an ACE inhibitor in patients with heart failure.⁷²

Agents that increase the expression of eNOS either directly or via risk-factor modification can, therefore, potentially have an additive or synergistic effect in improving endothelial function when coadministered with a PDE5 inhibitor, since the latter operates downstream of eNOS. This notion has also been shown to extend to improvement in erectile function.⁷³ Whether lifestyle interventions work in synergy with PDE5 inhibitors in improving coronary and peripheral endothelial function remains unknown. Other agents that have been known to improve endothelial function as well as ED include l-arginine, tetrahydrobiopterin and antioxidant supplements.⁵³

The Princeton consensus: erectile dysfunction and cardiology

In 1999, the first Princeton consensus addressed the cardiac safety of drug treatment for ED.⁷⁴ The 2006 revised guidelines expand upon this issue, recommending stratification of the risk, ideally including exercise electrocardiography, before resuming sexual activity.³⁸ In men with coronary artery disease, no adverse effect on cardiac ischemia has been observed with PDE5 inhibitors alone.⁷⁵ The randomized controlled trials of sildenafil identified no excess risk for myocardial infarction in those men randomized to active medication.⁷⁶ The interaction between PDE5 inhibitors and NO donors—typically nitrates—is, however, again highlighted for its potential high risk of precipitating hypotension.⁷⁶

In the setting of angina, alternatives to nitrates should be used after PDE5 inhibitor therapy. For the minority of patients whose cardiac risk from sexual activity is high, tadalafil should not be the PDE5 inhibitor of first choice, because of its long half-life. Although the second Princeton consensus contains recommendations as to how soon nitrate therapy can be used after the use of PDE5 inhibitors, no recommendations were made for the situation in reverse. Ongoing therapy with nitrates, especially long-acting nitrates, remains an absolute contraindication to the use of PDE5 inhibitors. If the patient's need for short-acting sublingual nitrate is infrequent, however, it can be argued that the judicious use of PDE5 inhibitors is reasonable, provided there has been an interval of at least 24 h from previous nitrate use.⁷⁷

Consistent with this Review, the revised guidelines recognize the role of endothelial dysfunction as the 'common denominator' for both ED and CVD. ED is highlighted as a risk marker for CVD in men with no cardiac symptoms and as an opportunity to institute cardiovascular preventative therapy. Recommendations state that any man presenting with ED should have estimation of correctable cardiovascular risk markers—lipids, glucose and blood pressure—with or without an exercise stress test for risk stratification. These guidelines are a major development in the recognition of the significance of ED, and establish a new precedent and challenge for CVD prevention.

Conclusions and implications for clinical practice

Erectile and endothelial dysfunction are common abnormalities that coexist in individuals with multiple cardiovascular risk factors and in those with established CVD. The mechanisms for erectile and endothelial dysfunction are closely related to the pathobiology of NO as a consequence of disturbances in the expression and activation of eNOS. Both erectile and endothelial dysfunction can be readily identified, although currently this is seldom routine clinical practice. Both conditions are predictive of cardiovascular events. The 'artery size' hypothesis is based on a structural notion, but is still consistent with generalized endothelial dysfunction underpinning these clinical disorders. ED has been associated with endothelial dysfunction of conduit vessels, increased coronary artery calcification and silent angina independent of traditional cardiovascular risk factors.

ED could potentially be employed as an independent predictor of cardiovascular risk to guide a targeted approach to identifying and modifying established and less well-established cardiovascular risk factors. Both erectile and endothelial dysfunction are responsive to lifestyle modification, particularly in patients who are obese and have the metabolic syndrome. Many drugs that improve endothelial function can also improve ED, but the effects are not universal. Correction of multiple cardiovascular risk factors, particularly with lifestyle changes, could be required to improve both conditions. PDE5 inhibitors also provide a powerful therapeutic tool for improving both erectile and endothelial dysfunction, with several cardiac applications.⁷⁸ Further studies should explore the efficacy of combination therapies with other agents used to modify cardiovascular risk status.

As recommended by the revised Princeton consensus, the strong link between erectile and endothelial dysfunction indicates that all patients complaining of ED, judged likely to be vasculogenic, should be screened for modifiable cardiovascular risk factors, and possibly subclinical atherosclerosis, using carotid ultrasonography, coronary calcium scores and an exercise stress test. Increased carotid intimal-medial thickness could be used to guide the intensity of risk factor intervention.⁷⁹ In patients with diabetes, the presence of ED can also provide a rationale for screening for silent coronary artery disease.⁴⁷ Clinicians need to consider and detect ED in their patients, and in so doing seize a unique opportunity for preventing CVD.

References

1. NIH Consensus Development Panel on Impotence (1993) Impotence. JAMA 270: 83–90 | PubMed | ISI |
2. Shabsigh R and Anastasiadis AG (2003) Erectile dysfunction. Annu Rev Med 54: 153–168 | Article | PubMed | ISI | ChemPort |
3. Montorsi P et al. (2004) Common grounds for erectile dysfunction and coronary artery disease. Curr Opinion Urol 14: 361–365 | ISI |
4. Corbin JD et al. Phosphodiesterase-5 inhibitors: importance to the cardiovascular system. In Contemporary Cardiology: Heart Disease and Erectile Dysfunction, 117–137 (Ed Kloner RA) Totowa: Humana Press Inc.
5. Andersson KE and Wagner G (1995) Physiology of penile erection. Physiol Rev 75: 191–236 | PubMed | ISI | ChemPort |
6. Traish AM and Guay AT (2006) Are androgens critical for penile erections in humans? Examining the clinical and preclinical evidence. J Sex Med 3: 382–407 | Article | PubMed | ChemPort |
7. Burnett AL (1997) Nitric oxide in the penis: physiology and pathology. J Urol 157: 320–324 | Article | PubMed | ISI | ChemPort |
8. Maas R et al. (2002) The pathophysiology of erectile dysfunction related to endothelial dysfunction and mediators of vascular function. Vasc Med 7: 213–225 | Article | PubMed | ISI |
9. Saenz de Tejada I et al. (2004) Physiology of erectile function. J Sex Med 1: 254–265 | Article | PubMed | ChemPort |
10. Hurt KJ et al. (2002) Akt-dependent phosphorylation of endothelial nitric-oxide synthase mediates penile erection. Proc Natl Acad Sci USA 99: 4061–4016 | Article | PubMed | ChemPort |
11. Burnett AL (2004) Novel nitric oxide signaling mechanisms regulate the erectile response. Int J Impot Res 16: S15–S19 | Article | PubMed | ISI | ChemPort |
12. Solomon H et al. (2003) Erectile dysfunction and the cardiovascular patient: endothelial dysfunction is the common denominator. Heart 89: 251–253 | Article | PubMed | ISI | ChemPort |
13. Bortolotti A et al. (1997) The epidemiology of erectile dysfunction and its risk factors. Int J Androl 20: 323–334 | Article | PubMed | ISI | ChemPort |
14. Bonetti PO et al. (2003) Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol 23: 168–175 | Article | PubMed | ISI | ChemPort |
15. Cooke JP and Dzau VJ (1997) Nitric oxide synthase: role in the genesis of vascular disease. Annu Rev Med 48: 489–509 | Article | PubMed | ChemPort |
16. Celermajer DS et al. (1994) Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction. J Am Coll Cardiol 24: 1468–1474 | PubMed | ISI | ChemPort |
17. Brunner H et al. (2005) Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension. J Hypertens 23: 233–246 | Article | PubMed | ISI | ChemPort |
18. Farouque HMO and Meredith IT (2001) The assessment of endothelial function in humans. Coron Artery Dis 12: 445–454 | Article | PubMed | ChemPort |
19. Vita JA and Keaney JF Jr (2002) Endothelial function: a barometer for cardiovascular risk? Circulation 106: 640–642 | Article | PubMed |
20. Lyons D et al. (1997) Impaired nitric oxide-mediated vasodilatation and total body nitric oxide production in healthy old age. Clin Sci (Lond) 93: 519–525 | PubMed | ChemPort |
21. Cooke JP (2005) ADMA: its role in vascular disease. Vasc Med 10 (Suppl): S11–S17 | Article |
22. Katusic ZS (2001) Vascular endothelial dysfunction: does tetrahydrobiopterin play a role? Am J Physiol Heart Circ Physiol 281: H981–H986 | PubMed | ISI | ChemPort |
23. Elesber AA et al. (2006) Coronary endothelial dysfunction is associated with erectile dysfunction and elevated asymmetric dimethylarginine in patients with early atherosclerosis. Eur Heart J 27: 824–831 | Article | PubMed | ISI | ChemPort |
24. Foresta C et al. (2005) Circulating endothelial progenitor cells in subjects with erectile dysfunction. Int J Impot Res 17: 288–290 | Article | PubMed | ISI | ChemPort |
25. Wierzbicki AS et al. (2006) Asymmetric dimethyl arginine levels correlate with cardiovascular risk factors in patients with erectile dysfunction. Atherosclerosis 185: 421–425 | Article | PubMed | ISI | ChemPort |
26. Grundy SM et al.; American Heart Association; National Heart, Lung, and Blood Institute (2005) Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 112: 2735–2752 | Article | PubMed | ISI |
27. Rosen RC et al. (1999) Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res 11: 319–326 | Article | PubMed | ISI | ChemPort |
28. Cappelleri JC et al. (1999) Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function. Urology 54: 346–351 | Article | PubMed | ISI | ChemPort |
29. Walczak MK et al. (2002) Prevalence of cardiovascular risk factors in erectile dysfunction. J Gend Specif Med 5: 19–24 | PubMed |
30. Wei M et al. (1994) Total cholesterol and high density lipoprotein cholesterol as important predictors of erectile dysfunction. Am J Epidemiol 140: 930–937 | PubMed | ISI | ChemPort |
31. Feldman HA et al. (1994) Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 151: 54–61 | PubMed | ISI | ChemPort |
32. Feldman HA et al. (2000) Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts male aging study. Prev Med 30: 328–338 | Article | PubMed | ISI | ChemPort |
33. Greenstein A et al. (1997) Does severity of ischemic coronary disease correlate with erectile function? Int J Impot Res 9: 123–126 | Article | PubMed | ISI | ChemPort |
34. Kloner RA et al. (2003) Erectile dysfunction in the cardiac patient: how common and should we treat? J Urol 170 (Suppl): S46–S50 | Article |
35. Solomon H et al. (2003) Relation of erectile dysfunction to angiographic coronary artery disease. Am J Cardiol 91: 230–231 | Article | PubMed | ISI |
36. Montorsi F et al. (2003) Erectile dysfunction prevalence, time of onset and association with risk factors in 300 consecutive patients with acute chest pain and angiographically documented coronary artery disease. Eur Urol 44: 360–364 | Article | PubMed | ISI |
37. Chiurlia E et al. (2005) Subclinical coronary artery atherosclerosis in patients with erectile dysfunction. J Am Coll Cardiol 46: 1503–1506 | Article | PubMed |
38. Jackson G et al. (2006) The second Princeton consensus on sexual dysfunction and cardiac risk: new guidelines for sexual medicine. J Sex Med 3: 28–36 | Article | PubMed | ChemPort |
39. Esposito K et al. (2005) High proportions of erectile dysfunction in men with the metabolic syndrome. Diabetes Care 28: 1201–1203 | Article | PubMed | ISI |
40. Giugliano F et al. (2004) Erectile dysfunction associates with endothelial dysfunction and raised proinflammatory cytokine levels in obese men. J Endocrinol Invest 27: 665–669 | PubMed | ISI | ChemPort |
41. Kato M et al. (2000) Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation 102: 2607–2610 | PubMed | ChemPort |
42. Margel D et al. (2004) Severe, but not mild, obstructive sleep apnea syndrome is associated with erectile dysfunction. Urology 63: 545–549 | Article | PubMed |
43. De Angelis L et al. (2001) Erectile and endothelial dysfunction in Type II diabetes: a possible link. Diabetologia 44: 1155–1160 | Article | PubMed | ISI | ChemPort |
44. Thompson IM et al. (2005) Erectile dysfunction and subsequent cardiovascular disease. JAMA 294: 2996–3002 | Article | PubMed | ISI | ChemPort |
45. Uslu N et al. (2006) Left ventricular diastolic function and endothelial function in patients with erectile dysfunction. Am J Cardiol 97: 1785–1788 | Article | PubMed | ChemPort |
46. Kaya C et al. (2006) Is endothelial function impaired in erectile dysfunction patients? Int J Impot Res 18: 55–60 | Article | PubMed | ISI | ChemPort |
47. Gazzaruso C et al. (2004) Relationship between erectile dysfunction and silent myocardial ischemia in apparently uncomplicated type 2 diabetic patients. Circulation 110: 22–26 | Article | PubMed | ISI |
48. Kaiser DR et al. (2004) Impaired brachial artery endothelium-dependent and -independent vasodilation in men with erectile dysfunction and no other clinical cardiovascular disease. J Am Coll Cardiol 43: 179–184 | Article | PubMed | ISI |
49. Bocchio M et al. (2004) Endothelial cell activation in men with erectile dysfunction without cardiovascular risk factors and overt vascular damage. J Urol 171: 1601–1604 | Article | PubMed | ISI |
50. Stuckey BGA et al. (2006) Erectile dysfunction predicts generalized cardiovascular disease: evidence from a case-control study. Atherosclerosis [doi:doi: 10.1016/j.atherosclerosis.2006.08.043] | Article |
51. Montorsi P et al. (2005) The artery size hypothesis: a macrovascular link between erectile dysfunction and coronary artery disease. Am J Cardiol 96 (Suppl 2): 19M–23M | Article |
52. Bonetti PO et al. (2003) Statin effects beyond lipid lowering—are they clinically relevant? Eur Heart J 24: 225–248 | Article | PubMed | ISI | ChemPort |
53. Woodman RJ et al. (2005) Mechanisms, significance and treatment of vascular dysfunction in type 2 diabetes mellitus: focus on lipid-regulating therapy. Drugs 65: 31–74 | Article | PubMed | ChemPort |
54. Esposito K et al. (2004) Effect of lifestyle changes on erectile dysfunction in obese men: a randomized controlled trial. JAMA 291: 2978–2984 | Article | PubMed | ISI | ChemPort |
55. Esposito K et al. (2006) Mediterranean diet improves erectile function in subjects with the metabolic syndrome. Int J Impot Res 18: 405–410 | Article | PubMed | ChemPort |
56. Margel D et al. (2005) Predictors of erectile function improvement in obstructive sleep apnea patients with long-term CPAP treatment. Int J Impot Res 17: 186–190 | Article | PubMed | ChemPort |
57. Rizvi K et al. (2002) Do lipid-lowering drugs cause erectile dysfunction? A systematic review. Fam Pract 19: 95–98 | Article | PubMed | ISI |
58. Bruckert E et al. (1996) Men treated with hypolipidaemic drugs complain more frequently of erectile dysfunction. J Clin Pharm Ther 21: 89–94 | PubMed | ISI | ChemPort |
59. Solomon H et al. (2006) Erectile dysfunction and statin treatment in high cardiovascular risk patients. Int J Clin Pract 60: 141–145 | Article | PubMed | ChemPort |
60. Pedersen TR and Faergeman O (1999) Simvastatin seems unlikely to cause impotence. BMJ 318: 192
61. Herrmann HC et al. (2006) Can atorvastatin improve the response to sildenafil in men with erectile dysfunction not initially responsive to sildenafil? Hypothesis and pilot trial results. J Sex Med 3: 303–308 | Article |