The molecular mechanisms for sympathetic regulation of cardiac function

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We have investigated the molecular mechanisms for the regulation of cardiac function by the sympathetic nervous system. For this purpose, we have used newly synthesized P-site inhibitor derivatives and transgenic mouse model in which the expression of type 5 adenylyl cyclase, the major cardiac isoform, is disrupted. We have conducted computer-assisted, drug screening by the use of pharma-core analysis as well as the analysis of the 3D structure of the enzyme protein and miscellaneous compounds. Similarly, we have examined potential changes in cardiac function and the regulation by the sympathetic nervous system in mice with the disrupted type 5 adenylyl cyclase gene.Most importantly, we have found that by modifying the side chains of classical P-site inhibitors, we can convert them into an adenylyl cyclase isoform-selective inhibitor. In particular, PM6, one of such compounds we have discovered, has demonstrated a high selectivity to the type 5 adenylyl cyclase isoform over other isofo … More rms. Accordingly, the treatment of cardiac myocytes in the presence of this compound significantly attenuated the development of cardiac myocyte apoptosis in response to prolonged catecholamine stimulation. Cardiac myocyte contractility was, however, unaffected, suggesting that this compound can inhibit the development of apoptosis without deteriorating cardiac function. It is thus tentative to speculate that such compound may be useful in the treatment of congestive heart failure, in which beta-adrenergic blockade therapy has been used.In mice with disrupted type 5 adenylyl cyclase gene, we have found that sympathetic regulation is attenuated on the top of diminished parasympathetic regulation. These findings suggest that type 5 adenylyl cyclase plays a major role in not only regulating sympathetic regulation, but parasympathetic regulation of the heart. We have also examined the effect of chronic catecholamine infusion in adenylyl cyclase-null mice. We have found that the development of cardiac myocyte apoptosis was significantly attenuated in knockout mice as well. Less