Current Pharmaceutical Design - Volume 14, Issue 35, 2008

Advances in genomics and proteomics have uncovered an expansive array of site-specific properties of the endothelium. Amongst the physiological role of endothelium, it mediates vasomotor tone, regulates cellular and nutrient trafficking, maintains blood fluidity, contributes to the local balance between pro- and anti-inflammatory mediators as well as procoagulant and anticoagulant activity, participates in generation of new blood vessels, and undergoes programmed cell death. Such heterogeneity provides the endothelium with remarkable flexibility and the capacity to respond to the unique needs of the underlying tissue. Endothelial dysfunction occurs in a variety of pathological conditions in internal medicine, such as atherosclerosis, hypercholesterolemia, type2-diabetes/metabolic syndrome, hypertension, heart failure, cigarette smoking, recreational drugs abuse; the incidence of sexual dysfunctions in such conditions is much increased. The reciprocal relationship between endothelial dysfunction and sexual medicine is based on the scientific agreement that erectile dysfunction (ED), benign prostatic hyperplasia and Peyronie's disease are believed to be vascular diseases in which endothelial dysfunction represents one of the common etiological factors. Despite this, drugs improving endothelial function, i.e. anti-hypertensives, statins, antioxidants etc. are able to prevent the progression of atherosclerosis but mildly improve erectile function per se since they lack specificity of action at the level of the penile vasculature and smooth muscle cells. Phosphodiesterase type-5 inhibitors (PDE5-i) are a class of new on-demand drugs that have revolutionized the treatment of male ED [1]. Sildenafil began as a potential alternative agent to oral nitrates for the treatment of stable angina pectoris, but its short half-life and modest nitratelike hemodynamic effects were not seen as a clinical advance. During chronic dosing studies, improved erections were reported, and this led to sildenafil development as a treatment for ED over ten years ago. Soon further, research has focused on more potent (vardenafil) and long-acting (tadalafil) drugs belonging to the same pharmacologic class, in order to accomplish different patients' requests. Their oral acceptability and success rate rapidly moved them into the treatment of first choice for most men with ED. Evidence-based medicine regarding alternative PDE5-i dosing e.g. once-a-day is now growing. This issue of Current Pharmaceutical Design focuses on the most recent knowledge regarding clinical correlates between sexual and internal medicine. Vlachopoulos et al. [2] report about the frequent association between endothelial dysfunction, atherosclerosis and ED, suggesting that this latter condition carries an incremental risk for future cardiovascular events; symptoms of ED may precede clinical cardiac manifestations usually by 3-4 years. They conclude that ED symptoms should prompt cardiac risk assessment. Ghiadoni et al. [3] remind us that no available test to assess endothelial function has sufficient sensitivity and specificity to be used yet in clinical practice. They conclude that only once a specific and affordable test has been validated, and definite evidence becomes available to demonstrate that endothelial dysfunction must be a target of pharmacological treatment, the evaluation of endothelium-dependent vasodilation would be included in the list of clinical examinations for assessing early vascular alterations also in patients at risk for developing ED. The cerebral and peripheral vasculatures are a target tissue for sex steroid hormones which play an important role in maintaining endothelial health; sex steroid deficiency is associated with endothelial dysfunction, vascular disease and ED. Traish et al. [4] suggest that clinical conditions such as metabolic syndrome, obesity or type-2 diabetes mellitus are associated with sexual steroid hormone insufficiency, and this may determine a dysregulation of endothelial function thus contributing to the pathogenesis of ED. Whether adipose tissue accumulation is able to inhibit testosterone production or decreasing testosterone levels with ageing may contribute to visceral obesity and increased CVD incidence is not known yet. The role of adipose tissue deposition and increased waist circumference in men seems to be the predominant mechanism that predisposes to metabolic disorders in which insulin resistance plays a central role. To this purpose, Potenza and Montagnani [5] discuss on the role of insulin physiology in determining correct endothelial functioning. Interestingly, they demonstrate that derangement of the insulin signaling into the cell leads to insulin resistance/endothelial dysfunction which precedes structural changes and clinical appearance of cardiovascular complications. Also, they propose ED as a sentinel symptom in patients with insulin resistance conditions.

Endothelial dysfunction is an important process in the development of atherosclerotic cardiovascular disease, while it is also a major pathophysiological mechanism underlying vasculogenic erectile dysfunction (ED). Expectedly, these two prevalent disorders are linked also at the clinical level: ED is common in patients with overt and silent coronary artery disease, while ED is increasingly being regarded as the early clinical manifestation of a generalized vascular disease and carries an independent risk for future cardiovascular events. The emerging awareness of ED as a barometer for cardiovascular disease offers a unique opportunity to enhance preventive vascular health in men. Lifestyle and risk factor modification, as well as pharmacologic therapy (both phosphodiesterase type-5 inhibitors and non-ED-targeting drugs), appear to confer additional benefit both in terms of ED treatment and overall cardiovascular risk; this benefit may be related, at least partly, to the improvement of endothelial function and anti-inflammatory effects. The present review identifies pathophysiologic links between endothelial dysfunction, ED and coronary artery disease, presents methodological aspects regarding penile and systemic endothelial function, and discusses the clinical implications in terms of diagnosis of ED, assessment of patient risk, and treatment.

The endothelium is not merely a barrier but it plays a key role in the maintenance of vascular homeostasis. A dysfunctional endothelium is an early marker of the development of atherosclerotic changes and can also contribute to cardiovascular events. Vascular reactivity tests represent the most widely used methods in the clinical assessment of endothelial function and in the last two decades, several methodologies were developed to study it non invasively in the peripheral macrocirculation (conduit arteries) and microcirculation (resistance arteries and arterioles). This review will centre on the most relevant available non-invasive techniques in the research on endothelial function, their advantages and limitations. Flow mediated dilation (FMD) of the brachial artery by ultrasounds is the most widely used vascular test to assess endothelium- dependent vasodilation. Other approaches include measurement of microcirculatory reactive hyperaemia by forearm venous pletysmography or digital pulse amplitude tonometry, response to β2 agonist by applanation tonometry or digital photoplethysmography and several test by skin laser doppler. It appears that FMD is the most reproducible test when an appropriate and accurate methodology is applied. Recently, post-ischemic vasodilation in the cavernous arteries was also suggested to study endothelial function in patients with erectile dysfunction. Systemic markers proposed as measures of NO biology, inflammatory cytokines, adhesion molecules, or markers of endothelial damage and repair have only a very limited role as a result of biological and assay availability and variability, these factors currently have a limited role in the assessment of individual patients. The optimal methodology for investigating the multifaceted aspects of endothelial dysfunction is still under debate. Therefore, no available test to assess endothelial function has sufficient sensitivity and specificity to be used yet in clinical practice. Only the growing concordant results from different reproducible and reliable non-invasive methods exploring endothelial function with different stimuli will support and strengthen experimental findings, thus providing conclusive answers in this area of research.

Erectile function is a complex neurovascular process that depends on the health of the central and peripheral nervous systems and the vasculature. Thus, signaling from the central nervous system (brain) to the peripheral nervous system (penis) is critical and is modulated by a set of complex interactions that depend on cerebral and vascular circulation. The cerebral and peripheral vasculatures are target tissues for sex steroid hormones. Gonadal, adrenal and neurosteroids regulate the function and physiology of the endothelium and modulate vascular and cerebral circulation by genomic and non-genomic dependent mechanisms. Recent advances in cell and molecular biology have defined a critical role of endothelium in vascular function. A host of biochemical and clinical markers of endothelium function and dysfunction have been identified to assess vascular pathology. Emerging evidence suggests that sex steroid hormones play an important role in maintaining endothelial health and sex steroid deficiency is associated with endothelial dysfunction, vascular disease and erectile dysfunction. Such information has important clinical implications in patient management with sex steroid hormone insufficiency, diabetes, metabolic syndrome, vascular disease and erectile dysfunction. In this review, we discuss the role of sex steroid hormones in modulation of the biochemical and clinical markers associated with endothelial dysfunction. Specifically the regulation of endothelial nitric oxide synthase, assymetric dimethylarginine, reactive oxygen species, endothelin-1, inflammatory cytokines, tumor necrosis factor-α, markers of cell adhesion, dysregulation of fibrinolytic factors and the inability to regenerate from endothelial progenitor cells concomitant with increased endothelial apoptosis, increased cellular permeability and increased vascular tone.

Coronary Artery Disease (CAD) and erectile dysfunction (ED) are cardiovascular complications frequently occurring in patients with diabetes, obesity, and dyslipidemia. All these metabolic disorders are characterized by insulin resistance, defined as decreased sensitivity and/or responsiveness to metabolic actions of insulin promoting glucose disposal. Insulin resistance is not only a hallmark of metabolic abnormalities, but also a prominent feature of haemodynamic disorders. Indeed, insulin-stimulated release of endothelial factors takes part into the physiological regulation of vascular function, and altered insulin actions may profoundly affect cardiovascular homeostasis under metabolic derangement. The signpost of impaired vascular reactivity is endothelial dysfunction, a condition in which the endothelium loses its physiological ability to produce the vasodilator nitric oxide (NO). A number of molecular, cellular, physiological, and clinical studies have indicated that insulin resistance may impair NO release and damage endothelial function through several patho-physiological mechanisms reciprocally interconnected. Although considered the earliest marker of impaired vascular health, endothelial dysfunction is initially asymptomatic; additional changes in the vessel structure are usually required before vascular complications manifest. Nevertheless, endothelial dysfunction may become clinically evident when endothelial-mediated relaxation is necessary and sufficient to exert a specific effect. ED may be the first expression of endothelial dysfunction, and therefore represents a sentinel event in the clinical appearance of silent CAD. Thus, insulin resistance triggers endothelial dysfunction, and endothelial dysfunction may manifest as ED long before CAD or other vascular complications become clinically evident. This review briefly outlines the main characteristics of endothelial function and dysfunction, and describes the signaling pathways involved in cardiovascular actions of insulin under physiological and pathological conditions. Moreover, potential cellular and molecular mechanisms linking insulin resistance to early CAD-ED detection are also illustrated.

Aldosterone is a steroid hormone that controls blood pressure by binding to the mineralocorticoid receptor (MR), a ligand-activated transcription factor, and regulating genes that play a role in salt and water homeostasis in the kidney. Dysregulation of the mineralocorticoid system reveals its crucial role in various human diseases including hypertension, atherosclerosis, cardiac failure, mineralocorticoid resistance, and disorders of the nervous system. Recently, experimental animal models of mineralocorticoid/salt-induced hypertension and atherosclerosis have revealed an epithelial, pro-inflammatory role for MR activation. Extensive investigation has begun to elucidate the mechanisms underlying the vascular effects of MR activation which involve its direct role in cardiomyocytes, vascular smooth muscle cells, and endothelial cells. More specifically, in patients with cardiovascular risk factors and disease, including diabetes, hypertension, and/or congestive heart failure, an excess of MR activation has been shown to have a negative impact on endothelial function hence disrupting the physiological balance between vasoconstriction and vasodilation. Such a mechanism may play a role in the pathogenesis of erectile dysfunction (ED), a condition that occurs frequently in patients with increased cardiovascular risk and involves endothelial dysregulation of vascular relaxation. The aim of this review is to summarize the latest concepts in MR signaling, with particular attention to the endothelium, and to discuss the potential benefits of tissue-selective MR blockade in treating subsets of ED patients, such as those with congestive heart failure and hypertension, in which the MR system may be over activated.

Endothelial dysfunction (EtD) has emerged as a critical master pathway in the pathogenesis of both vascular disease and erectile dysfunction (ED). Drugs that have been developed for vascular diseases and/or found to have beneficial endothelial effects may be helpful in the management of ED. In this manuscript we summarize the current state of the art with respect to endothelial active drugs and discuss the evidence supporting their use in the management of ED. Pubmed query for the terms Endothelial dysfunction, erectile dysfunction, pharmaceuticals, “endothelium”, “function”, “pharmaceutical”, “eNOS”, “erectile dysfunction” and “erectile function” was conducted. Relevant articles were reviewed and summarized. A variety of cardiovascular medications have mechanisms of action that involve the endothelium. Examples include HMG-CoA Reductase inhibitors (“statins”), Angiotensin Converting Enzyme Inhibitors (ACEI), Angiotensin Receptor blockers (ARB), Endothelin Receptor Antagonists (ERA), certain beta blockers, and some oral hypoglycemics. Some of these drugs have been found to improve penile erection, although an endothelium dependent mechanism has not been conclusively demonstrated in all studies. Drugs that improve endothelial function in the cavernous arteries and the erectile tissues of the corpora cavernosa hold great promise in treating or at least minimizing the vascular damage that contributes to ED. ACEI and ARB appear to hold great promise in this regard, while statins and oral hypoglycemics may play a potentially useful role as adjunctive therapy for ED. Improvements in endothelial function may help reverse ED in some cases, which would be a marked improvement over management with currently available “on demand” ED therapies.

Erectile dysfunction (ED) and endothelial dysfunction are common in individuals with multiple cardiovascular risk factors (CRFs) and are longitudinal predictors of cardiovascular events. ED is associated with systemic endothelial cell activation/dysfunction independent from CRFs or from diffuse, unrecognized vascular damage. The pathogenesis of endothelial dysfunction and ED is intimately linked through decreased expression and activation of endothelial nitric oxide (NO) synthase and the subsequent physiologic actions of NO. Furthermore, reduced biologic activity of endotheliumderived NO links atherosclerosis to ED and underscores the role of altered endothelium in the pathogenesis of both conditions. Evidence-based data suggest that daily use of phosphodiesterase type-5 inhibitors (PDE5-i) improves endothelial and erectile functions and that this benefit is lost upon drug withdrawal. Daily PDE5-i may also improve lower tract urinary symptoms related to benign prostatic hyperplasia through a reduction of adrenergic overtone. The relevance for these drugs in the prevention of complications in internal medicine diseases, i.e. cardiovascular disease, clotting disorders and autoimmune disease is uncertain. Finally, endothelial dysfunction is present in testosterone deficiency syndromes and replacement therapy is able to revert ED and to improve endothelial function. Aim of the present review is to discuss the systemic effects of drugs designed to treat ED, such as testosterone and PDE5- i, with regard to safety, unwanted effects and efficacy in improving endothelial function; finally, a goal-oriented approach to rehabilitation using daily vs. on-demand PDE5-i in difficult patients is discussed.