REGULATION OF CARDIAC SECOND MESSENGERS BY ANGIOTENSIN

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The renin-angiotensin system is a major regulator of fluid and volume homeostasis in mammalian species. In pathological processes such as hypertension and congestive heart failure, inhibition of angiotensin converting enzyme results in decreased levels of angiotensin II and provides beneficial clinical effects. Human studies, in which the angiotensin II receptor antagonist, saralasin, was used to decrease vascular resistance, showed reduction in cardiac output indicating that angiotensin II may be an in vivo modulator of cardiac contractile function. In cardiac tissue angiotensin II participates in the regulation of transmembrane signalling and cardiac muscle cell growth. The cardiac effects of angiotensin II could be mediated by circulating peptide produced by the peripheral renin-angiotensin system or a locally active system in the heart. Identification of the precursor genes for the renin angiotensin system in the heart and quantifiable production of translatable product (angiotensin II) suggests that mechanical and humoral regulation of a localized renin angiotensin system could have significant implications for angiotensin II-mediated responses in cardiac tissue. Inhibition of the angiotensin II-mediated hypertrophic response in neonatal rat cardiomyocytes by the protein kinase C inhibitor, staurosporin, suggests that angiotensin II stimulated increases in second messengers may be integrally involved in cardiac growth processes. We propose to determine if the angiotensin II-stimulated increases in cytosolic free Ca2+, inositol phosphates, and diacylglycerol-protein kinase C are mediated by one or multiple membrane receptors, and to characterize the time course for these responses. The putative guanine nucleotide binding proteins that couple angiotensin II receptors to effector responses will be determined using pharmacologic manipulation with cholera and pertussis toxins. We have hypothesized that protein kinase C is involved in mediating the cardiac hypertrophic growth response to angiotensin II. We will determine the subcellular distribution of specific protein kinase C isozymes and their regulation in nuclear and cytoskeletal fractions by angiotensin II and phorbol esters. These studies will provide a more complete understanding of the role of angiotensin peptides in the modulation of cardiac function at the level of second messengers.