Editorial [Hot Topic: Drugs Targeted to Improve Endothelial Function: Clinical Correlates Between Sexual and Internal Medicine (Executive Editor: Antonio Aversa)]

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.