The objective is to define the role of the natriuretic peptides (NPS) as a paracrine and autocrine system in cardiac regulation in human CHF. Our hypothesis is that during the evolution of CHF the activity of the local cardiac natriuretic peptide system is enhanced with augmented cGMP generation which could contribute to the myocardial cell and coronary vascular smooth muscle cell adaptations which characterize CHF. To address our working hypothesis, four Specific Aims are proposed: (l) To determine atrial and ventricular secretion and molecular forms of the three natriuretic peptides. in humans with CHF. (2) To localize, quantitate synthesis and determine molecular forms of the natriuretic peptides in the human heart in CHF. (3) To localize and quantitate cardiac cGMP production and the ability of the natriuretic peptides to stimulate production of cGMP in intact human myocardium in the absence and presence of CHF and in isolated human cardiac myocytes and coronary vascular smooth muscle cells. (4) To determine if antagonism of the natriuretic peptide clearance receptor and inhibition of neutral endopeptidase 24.11 potentiate cGMP accumulation in human myocardium in CHF and in isolated human cardiac myocytes and coronary vascular smooth muscle cells.
