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Patients with heart failure have reduced forearm vasodilator responses when endothelial cell nitric oxide production is stimulated by muscarinic agonists. The aim of this study was to determine if activity of the nitric oxide pathway was also abnormal under basal conditions. Forearm blood flow (FBF) was measured with strain-gauge plethysmography in response to the intraarterial infusion of a subsystemic dose range of L-N-monomethylarginine (L-NMMA), a competitive inhibitor of nitric oxide synthase. In 18 normal subjects, the baseline FBF of 3.6 [+ or -] 1.4 was decreased by 0.3 [+ or -] 0.5 (p >0.01), 1.0 [+ or -] 0.7 (p (Am J Cardiol 1994; 74:1133--1136)

The role of hypertension in the pathogenesis of renal damage is a subject of both historical interest and current investigation. Because of the difficulty associated with studying the pathophysiologic role of glomerular injury in systemic hypertension, experimental models have provided much of the data in this field. The mechanisms leading to glomerular injury are complex and not fully elucidated. Mesangial and endothelial cell injury are thought to be important pathophysiologic mechanisms in the renal injury associated with hypertension. One hypothesis suggests that glomerular hypertension (ie, a hemodynamic event) is the primary pathogenetic mechanism, but another supports the notion that glomerular hypertrophy (ie, abnormal growth-related events) contributes to injury. The intrarenal renin-angiotensin system may play an important pathogenetic role in end-stage renal disease. Angiotensin-converting enzyme (ACE) inhibition has been shown to arrest the progression of renal injury in animal models. Although the clinical database is incomplete, the findings of anecdotal reports and short-term studies suggest that ACE inhibition may preserve renal function in patients with scleroderma renal crisis, reduce proteinuria in patients with diabetic nephropathy, and normalize renal hemodynamics in patients with a variety of renal diseases. The beneficial effects of ACE inhibition may be due to both hemodynamic (eg, reduction in glomerular capillary and intraglomerular pressures) and nonhemodynamic (eg, potassium-sparing and reduction in mesangial proliferation) mechanisms. The precise role of ACE inhibitors in the prevention of renal damage awaits the results of ongoing long-term, double-blind clinical studies. Nevertheless, ACE inhibition may be an appropriate therapeutic alternative in the hypertensive patient whose renal injury is progressing despite aggressive antihypertensive therapy.

Patients with congestive heart failure demonstrate attenuated endothelium-dependent vasodilation of the peripheral vasculature, but there are no data regarding the effect of therapies on this abnormality or whether this abnormality is reversible. This study was performed to address the hypothesis that abnormalities in endothelium-dependent vasodilation in heart failure are improved by heart transplantation. Forearm blood flow responses to the intraarterial administration of a dose range of methacholine, an endothelium-dependent vasodilator, and nitroprusside, an endothelium-independent vasodilator, were examined in 2 separate protocols. In protocol 1, forearm blood flow responses to methacholine in 14 heart transplant recipients were 5.02 [+ or -] 3.11, 11.55 [+ or -] 7.20 and 11.61 * 10.24 ml/min/100 ml forearm volume. These responses were sigaificantly greater then those in 10 patients with heart failure (2.23 [+ or -] 1.22, 4.60 [+ or -] 3.43 and 6.70 [+ or -] 4.91 ml/min/100 ml forearm volume; p (Am J Cardiol 1993;71:88-93)

The functions of the endothelium and the effects of hypertension, atherosclerosis, and diabetes on the endothelium are reviewed. The endothelium affects vascular tone by releasing vasodilators and modulating the effects of vasoactive substances such as catecholamines, bradykinin, serotonin, and angiotensin II. Relaxation of vascular smooth muscle depends upon a functionally intact endothelium and the release of the endothelium-derived relaxing factor nitric oxide. Endothelial cells also appear to release a hyperpolarizing factor that relaxes smooth muscle through activation of the sodium-potassium pump, and of the endothelium-dependent contracting factors. Similarities are found in the vascular injury resulting from hypertension, atherosclerosis, and diabetes. When these risk factors coexist, they can act synergistically and magnify the vascular injury. The endothelium appears to be one of the major targets for these forms of injury. Future therapeutic strategies will focus on ways to prevent, arrest, or reverse endothelial injury., The endothelium is the layer of cells forming the inner lining of the blood vessels. It plays a very important role in the control of cardiovascular function. A variety of substances released from the endothelium under different conditions affect the responses to vasodilators such as prostacyclin, and to vasoconstrictors such as catecholamines, bradykinin, serotonin, and angiotensin II. (Vasodilators cause blood vessels to relax and vasoconstrictors cause them to contract.) One endothelial product that appears to be important in the regulation of blood pressure, among other functions, is endothelium-derived relaxing factor (EDRF). Another substance released by the endothelium is an as-yet unidentified factor that causes blood vessel relaxation by activating the transport of electrically charged ions across the membrane of the smooth muscle of the vascular system. The actions of these substances are dependent on the presence of an intact endothelium, and when this portion of the vasculature is damaged, disturbances in blood pressure regulation are often exacerbated. Several disease conditions can cause injury to the endothelium, including hypertension (high blood pressure), diabetes, and atherosclerosis (the formation of fatty plaque deposits on the inner surface of blood vessels). The endothelial damage caused by these various conditions is very similar, and may reflect a common mechanism. When these risk factors co-exist, a synergistic effect is often observed, and the degree of vascular injury is greater than the sum of the individual components. Arrest, prevention, and reversal of endothelial damage will be a major therapeutic focus in the future. (Consumer Summary produced by Reliance Medical Information, Inc.)