Activation of TxA2/PGH2Receptors and Protein Kinase C Contribute to Coronary Dysfunction in Superoxide Treated Rat Hearts

Abstract

S. A. Gupte, T. Okada, M. Tateyama and R. Ochi. Activation of TxA2/PGH2Receptors and Protein Kinase C Contribute to Coronary Dysfunction in Superoxide Treated Rat Hearts. Journal of Molecular and Cellular Cardiology (2000) 32, 937–946. We have previously shown that superoxide anion (O2−) stimulates the release of vasoconstrictor prostanoids and induces a prolonged rise in coronary perfusion pressure (CPP) that persists even after removal of O2−. In this study, we tested the hypothesis that the increased CPP is mediated by activation of TxA2/PGH2(TP) receptors and protein kinase C (PKC)-dependent mechanisms. In Langendorff perfused rat hearts, O2−was applied for 15 min and then washed out over a period of 20 min. Application of O2−increased the release of vasoconstrictive (TxA2and PGF2α) and decreased vasodilating (PGI2and PGE2) prostanoids. Although indomethacin (10 μ m), a cyclooxygenase inhibitor, attenuated the rise in CPP during O2−perfusion, the increase was not completely blocked. OKY 046Na (10 μ m), a thromboxane synthase inhibitor, had no effect on O2−-induced increases in CPP, whereas ONO 3708 (10 μ m), a TP receptor antagonist, suppressed this effect. PKC activity was also elevated by more than 50% by O2−perfusion. CPP typically increased throughout the O2−wash-out. This post-O2−vasoconstriction was not inhibited by indomethacin, nitroglycerin or nitrendipine. In contrast, ONO 3708 (10 μ m) and two PKC inhibitors, staurosporine (10 n m) and calphostin C (100 n m), completely blocked the rise in CPP, and even elicited vasodilation. PDBu enhanced the post-O2−vasoconstriction. We conclude that O2−-induced coronary vasoconstriction is initially mediated by TP receptors, but activation of PKC sustains the response.