ENDOTHELIAL FUNCTION AND DYSFUNCTION IN HEART-FAILURE

The endothelium controls vascular smooth muscle tone by secreting subs tances that cause relaxation and contraction. Under physiological, bas al conditions the endothelium constantly releases nitric oxide, a proc ess closely regulated by the effect of shear stress on endothelial cel ls. Recent data raise the possibility that, among many other substance s, bradykinin also plays an important role in the regulation of vascul ar tone. Bradykinin is a vasodilator that increases the activity of co nstitutive nitric oxide synthase, the enzyme that ultimately produces nitric oxide. Congestive heart failure (CHF) is a complex clinical syn drome in which abnormal vascular endothelial function has been shown t o occur at both the experimental and clinical level. The reduced nitri c oxide-mediated vasodilation in CHF is multifactorial. Constitutive n itric oxide synthase is downregulated as shear stress is reduced. Vasc ular angiotensin-converting enzyme (ACE), which produces angiotensin I I and inactivates bradykinin, is up-regulated. Angiotensin II is a pow erful vasoconstrictor, and the reduced availability of bradykinin will further down-regulate constitutive nitric oxide synthase. The CHF-ind uced activation of tumour necrosis factor also leads to a down-regulat ion of constitutive nitric oxide synthase and to an increased rate of endothelial-cell apoptosis. These observations suggest that abnormalit ies of endothelial function in CHF may contribute to increased periphe ral vasomotor tone both at rest and during exercise, and raise the pos sibility that the beneficial effects of ACE inhibition in CHF may be d ue in part to improved endothelial function.