Vascular and metabolic effects of candesartan: insights from therapeutic interventions

Abstract

Effects of angiotensin II type 1 receptor blockers (ARBs) to improve endothelial dysfunction may be due to mechanisms in addition to the reduction of high blood pressure per se. Endothelial dysfunction is characterized by vascular inflammation that contributes to clinically significant atherosclerosis and by an increased tendency for thrombus formation. Hypertensive patients have impaired endothelial functions that have positive predictive power with respect to future cardiovascular events. The present review will focus on multiple mechanisms underlying vascular and metabolic effects of ARBs that may synergize to prevent or regress atherosclerosis, onset of diabetes, and coronary heart disease. Angiotensin II accelerates the development of atherosclerosis by activating angiotensin II type 1 receptors that then promote superoxide anion generation and oxidative stress, leading to activation of nuclear transcription factor and endothelial dysfunction. Activation of angiotensin II type 1 receptors also stimulates increased expression of plasminogen activator inhibitor type 1 and tissue factor. Endothelial dysfunction associated with the metabolic syndrome and other insulin-resistant states is characterized by impaired insulin-stimulated production of nitric oxide from the endothelium and decreased blood flow to skeletal muscle. Increasing insulin sensitivity therefore improves endothelial function, and this may be an additional mechanism whereby ARBs decrease the incidence of coronary heart disease and the onset of diabetes. Adiponectin serves to link obesity with insulin resistance. In addition, adiponectin has anti-atherogenic properties.