The overall goal of this project is to examine the role of nitric oxide (NO) as a modulator of autonomic cardiac regulation, and to test the general hypothesis that abnormalities of NO regulation contribute to the autonomic abnormalities characteristic of heart failure. beta-adrenergic hyporesponsiveness and decreased parasympathetic tone are hallmarks of heart failure, and NO has properties that could contribute to these autonomic derangements. The heart expresses both constitutive and inducible forms of nitric oxide synthase (cNOS and iNOS, respectively). Whereas cNOS activity appears to be involved in both beta-adrenergic and cholinergic contractile responses, the induction of iNOS by cytokines or endotoxin depresses the beta-adrenergic contractile response. Intracoronary infusions of a specific NOS inhibitor will be used to assess the contribution of NO to beta-adrenergic and cholinergic contractile responses in conscious dogs before and after the induction of heart failure by rapid pacing and in patients with and without heart failure. The intracoronary infusion technique isolates the cardiac effects of NOS inhibition by reducing systemic responses. Specific aim 1 proposes to test the hypotheses that NO accounts for the development within the heart of 1) beta-adrenergic receptor pathway, 2) muscarinic receptor pathway, and 3) myocardial adenylyl cyclase abnormalities associated with the development of dilated cardiomyopathy in the dog. Specific aim 2 proposes to test the hypothesis that the NO pathway acts independently of the guanine-nucleotide binding protein signal transduction systems in influencing cardiac sympathetic-parasympathetic interactions. Specific aim 3 proposes to test in humans the hypotheses that NO may l) modulate parasympathetic-sympathetic interactions, 2) account, in part, for the adrenergic and 3) muscarinic abnormalities characteristic of human heart failure. The studies contained in this application should provide important new insights into the control of myocardial inotropic state in the normal and failing ventricle.