CARDIOVASCULAR CONTROL BY NITRIC OXIDE IN HEART FAILURE

点击翻译按钮获取中文摘要

The overall goal of this project is to examine in humans the role of nitric oxide (NO) in three aspects of normal myocardial and vascular regulation, and to test the general hypothesis that abnormalities of NO regulation contribute to the pathophysiology of patients with congestive heart failure (CHF). NO's role as a paracrine autacoid regulator of vascular tone is well appreciated, and increasing evidence now implicates abnormalities of NO-dependent regulation of the systemic and coronary vasculature in CHF. In normal myocardium, NO elaborated by microvascular endothelial cells an myocytes may affect cardiac myocyte function by modulating beta-adrenergic and muscarinic cholinergic responses. In certain pathologic states, cytokine-induced overexpression of myocardial NO may depress systolic and diastolic function. There is now reason to believe that abnormal NO regulation may contribute to several incompletely understood aspects of the pathophysiology of CHF. We will use local intracoronary and intrapulmonary artery infusions of NG-monomethyl-1-arginine (:L-NMMA), an inhibitor of NOS alone and in conjunction with a variety of chemical and physiologic stimuli, to address the role of NO in humans with CHF due to idiopathic and ischemic dilated cardiomyopathy, myocarditis and human immunodeficiency virus-related myocarditis/cardiomyopathy. For comparison, we will study humans with normal myocardial hemodynamic function. We will focus on three areas that have not previously been addressed in humans. In Specific Aim 1, we will test the hypotheses that 1) No plays a role in modulating basal and autonomically-mediated changes in systolic and diastolic myocardial function in normal humans, and 2) abnormal regulation of cardiac NO contributes to left ventricular dysfunction in patients with CHF due to several etiologies. In Specific Aim 2, we will test the hypotheses that 1) NO plays a role in metabolic coronary resistance vessel regulation in normal humans, and 2) abnormal NO regulation contributes to reduced metabolic stimulation of coronary blood flow in patients with idiopathic dilated cardiomyopathy. In Specific Aim 3, we will utilize a novel approach for the direct assessment of pulmonary vascular tone to test the hypotheses that 1) NO plays a role in regulating pulmonary vascular tone in normal humans, and 2) abnormal NO-dependent vasodilator function contributes to pulmonary hypertension in patients with CHF at rest and with increased pulmonary blood flow.