Endothelial nitric oxide pathway function in the peripheral vasculature of patients with heart failure

Many studies have investigated the pathophysiologic contributions of abnormalities in the endothelial nitric oxide pathway to the heightened vasoconstrictor tone that is characteristic of the clinical syndrome of heart failure. The most consistent abnormality is a reduced vasodilator response to muscarinic stimulation with either acetylcholine or methacholine, a finding which has been identified in several animal models of heart failure as well as in forearm and leg resistance vessels in patients with heart failure. More recent studies with desmopressin, a vasopressin 2 receptor agonist that stimulates nitric oxide production independent of the muscarinic receptor, have demonstrated that the abnormality in endothelium-dependent vasodilation was not limited to the muscarinic pathway. At present, the mechanisms of the defect in the endothelial nitric oxide pathway are unknown. But, they appear not to be directly related to sympathetic stimulation. Finally, studies using transplant recipients have demonstrated that this defect is reversible. In addition, a pilot study has demonstrated that supplemental oral L-arginine, the precursor for nitric oxide, has beneficial effects on forearm blood flow responses to exercise, arterial compliance nad functional status as assessed by increased distances during a 6-minute walk test and lower scores on the Living with Heart Failure Questionnaire. These studies suggest that the endothelial nitric oxide pathway may be a target for therapeutic interventions in heart failure.