Endothelial function and dysfunction in heart failure.

Abstract

The endothelium controls vascular smooth muscle tone by secreting substances that cause relaxation and contraction. Under physiological, basal conditions the endothelium constantly releases nitric oxide, a process closely regulated by the effect of shear stress on endothelial cells. Recent data raise the possibility that, among many other substances, bradykinin also plays an important role in the regulation of vascular tone. Bradykinin is a vasodilator that increases the activity of constitutive nitric oxide. Congestive heart failure (CHF) is a complex clinical syndrome in which abnormal vascular endothelial function has been shown to occur at both the experimental and clinical level. The reduced nitric oxide-mediated vasodilation in CHF is multifactorial. Constitutive nitric oxide synthase is downregulated as shear stress is reduced. Vascular angiotensin-converting enzyme (ACE), which produces angiotensin II and inactivates bradykinin, is up-regulated. Angiotensin II is a powerful vasoconstrictor, and the reduced availability of bradykinin will further down-regulate constitutive nitric oxide synthase. The CHF-induced activation of tumour necrosis factor also leads to a down-regulation of constitutive nitric oxide synthase and to an increased rate of endothelial-cell apoptosis. These observations suggest that abnormalities of endothelial function in CHF may contribute to increased peripheral vasomotor tone both at rest and during exercise, and raise the possibility that the beneficial effects of ACE inhibition in CHF may be due in part to improved endothelial function.