Activation of TxA2/PGH2 receptors and protein kinase C contribute to coronary dysfunction in superoxide treated rat hearts

• Published in: Journal of molecular and cellular cardiology Vol. 32; no. 6; pp. 937 - 946
• Main Authors: Gupte, S A, Okada, T, Tateyama, M, Ochi, R
• Format: Journal Article
• Language: English
• Published: England 01.06.2000
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology; Animals; Calcium Channel Blockers - pharmacology; Cardiovascular Agents - pharmacology; Coronary Disease - enzymology; Coronary Disease - metabolism; Dinoprost - pharmacology; Enzyme Inhibitors - pharmacology; In Vitro Techniques; Indomethacin - pharmacology; Male; Methacrylates - pharmacology; Naphthalenes - pharmacology; Perfusion; Prostaglandins - metabolism; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin - metabolism; Receptors, Thromboxane - metabolism; Receptors, Thromboxane A2, Prostaglandin H2; Staurosporine - pharmacology; Superoxides - metabolism; Thromboxane A2 - analogs & derivatives; Thromboxane A2 - metabolism; Thromboxane A2 - pharmacology; Thromboxane-A Synthase - antagonists & inhibitors; Vasoconstrictor Agents - pharmacology
• ISSN: 0022-2828
• DOI: 10.1006/jmcc.2000.1134

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 (TxA2 and PGF2alpha) and decreased vasodilating (PGI2 and PGE2) prostanoids. Although indomethacin (10 microM), a cyclooxygenase inhibitor, attenuated the rise in CPP during O2- perfusion, the increase was not completely blocked. OKY 046Na (10 microM), a thromboxane synthase inhibitor, had no effect on O2--induced increases in CPP, whereas ONO 3708 (10 microM), 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 microM) and two PKC inhibitors, staurosporine (10 nM) and calphostin C (100 nM), 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.