The reduced vasodilatory response to exercise in the peripheral circulation appears to be an important determinant of exercise intolerance in patients with severe congestive heart failure. Increased peripheral vasomotor tone in patients with congestive heart failure at rest and during exercise may be related to abnormalities in vascular endothelium function. Endothelial cell dysfunction appears to be characterized by decreased agonist-induced, endothelium-dependent, nitric oxide-mediated vasodilation and possibly increased release of the endothelium-derived vasoconstricting substance, endothelin-1. Whether abnormalities of vascular endothelial cell dysfunction directly contribute to the abnormal vascular response to exercise in patients with congestive heart failure has not been previously determined. Accordingly, the specific aims of this research proposal are (1) to investigate the role of endothelium-derived vasoactive substances in the pathophysiology of increased peripheral vasomotor tone at rest and during exercise in patients with congestive heart failure; (2) to determine whether abnormalities of nitric oxide metabolism contribute to the pathophysiology of abnormal endothelial regulation of peripheral vasomotor tone at rest and during exercise in patients with heart failure; and (3) to investigate the pathogenesis of vascular endothelial cell dysfunction by assessing changes in endothelial cell regulation of peripheral vasomotor tone and nitric oxide metabolism in response to therapy for heart failure. In a series of interrelated studies, endothelial cell regulation of peripheral vasomotor tone and nitric oxide metabolism will be assessed in patients with congestive heart failure and normal subjects with 3 methods: 1) measuring forearm blood flows (with venous occlusion plethysmography) at rest and in response to rhythmic handgrip exercise before and after administration of graded doses of L-NG- mono-methylarginine (L-NMMA, an inhibitor of nitric oxide synthesis) and bosentan (an endothelin receptor antagonist); 2) determining total body nitric oxide synthesis by measuring 15N-labeled metabolites of nitric oxide after an infusion of 15N-L-arginine (the amino acid metabolic precursor of nitric oxide) at rest and during exercise; and 3) measuring expression and activity of the inducible form of nitric oxide synthase in peripheral mononuclear phagocytes (macrophages) with molecular biology techniques. These three techniques will be applied to investigate endothelial regulation of peripheral vasomotor tone and nitric oxide metabolism before and after chronically increasing peripheral blood flow with a left ventricular assist device, before and after chronic angiotensin converting- enzyme inhibition, and before and after physical training. Increased understanding of the pathophysiologic changes in vascular endothelial cell function in patients with congestive heart failure, will enable more effective use of currently available drug treatments and facilitate the development of new therapeutic strategies. Correction of specific abnormalities in vascular endothelial cell function may serve as a target for future pharmacologic therapy development.
