The pathophysiology of erectile dysfunction related to endothelial dysfunction and mediators of vascular function

Nitric oxide (NO) released by vascular endothelial cells accounts for the relaxation of strips of vascular tissue and for the inhibition of platelet aggregation and platelet adhesion attributed to endothelium-derived relaxing factor. We now demonstrate that NO can be synthesized from L-arginine by porcine aortic endothelial cells in culture. Nitric oxide was detected by bioassay, chemiluminescence or by mass spectrometry. Release of NO from the endothelial cells induced by bradykinin and the calcium ionophore A23187 was reversibly enhanced by infusions of L-arginine and L-citrulline, but not D-arginine or other close structural analogues. Mass spectrometry studies using 15N-labelled L-arginine indicated that this enhancement was due to the formation of NO from the terminal guanidino nitrogen atom(s) of L-arginine. The strict substrate specificity of this reaction suggests that L-arginine is the precursor for NO synthesis in vascular endothelial cells.

Endothelial function is impaired in coronary artery disease and may contribute to its clinical manifestations. Increased oxidative stress has been linked to impaired endothelial function in atherosclerosis and may play a role in the pathogenesis of cardiovascular events. This study was designed to determine whether endothelial dysfunction and vascular oxidative stress have prognostic impact on cardiovascular event rates in patients with coronary artery disease. Endothelium-dependent and -independent vasodilation was determined in 281 patients with documented coronary artery disease by measuring forearm blood flow responses to acetylcholine and sodium nitroprusside using venous occlusion plethysmography. The effect of the coadministration of vitamin C (24 mg/min) was assessed in a subgroup of 179 patients. Cardiovascular events, including death from cardiovascular causes, myocardial infarction, ischemic stroke, coronary angioplasty, and coronary or peripheral bypass operation, were studied during a mean follow-up period of 4.5 years. Patients experiencing cardiovascular events (n=91) had lower vasodilator responses to acetylcholine (P<0.001) and sodium nitroprusside (P<0.05), but greater benefit from vitamin C (P<0.01). The Cox proportional regression analysis for conventional risk factors demonstrated that blunted acetylcholine-induced vasodilation (P=0.001), the effect of vitamin C (P=0.001), and age (P=0.016) remained independent predictors of cardiovascular events. Endothelial dysfunction and increased vascular oxidative stress predict the risk of cardiovascular events in patients with coronary artery disease. These data support the concept that oxidative stress may contribute not only to endothelial dysfunction but also to coronary artery disease activity.

To project the likely worldwide increase in the prevalence of erectile dysfunction (ED) over the next 25 years, and to identify and discuss some possible health-policy consequences using the recent developments in the UK as a case study. Using the United Nations projected male population distributions by quinquennial age groups for 2025, the prevalence rates for ED were applied from the Massachusetts Male Aging Study (MMAS) to calculate the likely incidence of ED. The MMAS has the advantage of being the first study to provide population-based rates rather than rates based on clinical samples. All the projections were age-adjusted. It is estimated that in 1995 there were over 152 million men worldwide who experienced ED; the projections for 2025 show a prevalence of approximately 322 million with ED, an increase of nearly 170 million men. The largest projected increases were in the developing world, i.e. Africa, Asia and South America. The likely worldwide increase in the prevalence of ED (associated with rapidly ageing populations) combined with newly available and highly publicized medical treatments, will raise challenging policy issues in nearly all countries. Already under-funded national health systems will be confronted with unanticipated resource requests and challenges to existing government funding priorities. The projected trends represent a serious challenge for healthcare policy makers to develop and implement policies to prevent or alleviate ED.