EFFECTS OF NEUROENDOCRINE FACTORS ON CARDIAC NA^+/CA^<2+> EXCHANGER

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Various neuroendocrine factors are known to be involved in heart failure.We tested the effects of isoproterenol, phanylephrine, angiotensine II and endotheline on Na^+/Ca^<2+> exchange (NCX) current but did not see any change in the current. Therefore we investigated not the membrane receptors but intracellular signaling pathways using guinea pig cardiac ventricular cells and H9c2 cells derived from rat cardiac myocytes. Combining the methods of the whole-cell voltage clamp, RT-PCR and the Western blot, the following themes were investigated.(1)Effects of acidic preconditioning on NCX.(2)Mechanism of activation of NCX by Reactive oxygen species.(3)Signaling pathways of modulation of NCX mRNA and protein.We obtained the following results. (1)Acidic preconditioning decreases NCX-NHE interaction via activation of PKCc and inhibits Ca^<2+> overload. (2)Two different pathways exist for activation of NCX by hydrogen peroxide. One is indirectly via activation of NHE. Another is via direct tyrosine phosphorylation of NCX by activating MEK. (3) A small G-protein Rho is involved in modulation of NCX mRNA expression. We will further pursue the projects to fully elucidate the mechanisms.