ono-3708 and Coronary-Disease

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.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Calcium Channel Blockers; Cardiovascular Agents; Coronary Disease; Dinoprost; Enzyme Inhibitors; In Vitro Techniques; Indomethacin; Male; Methacrylates; Naphthalenes; Perfusion; Prostaglandins; Protein Kinase C; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Staurosporine; Superoxides; Thromboxane A2; Thromboxane-A Synthase; Vasoconstrictor Agents

We studied the effects of a thromboxane A2 synthetase inhibitor (RS-5186), a thromboxane A2 antagonist (ONO-3708), a 5-lipoxygenase inhibitor (AA-861) and a peptidoleukotriene antagonist (ONO-1078) on infarct size, polymorphonuclear leukocyte infiltration, gross myocardial hemorrhage and arrhythmias in the canine coronary occlusion (2 hour)-reperfusion model (5 hour). The infarct size and risk area were determined by a double staining technique. Thirty minutes prior to occluding the coronary arteries, dogs were randomly assigned to one of the following five groups: the thromboxane A2 synthetase inhibitor group (n = 11) receiving RS-5186 10 mg/kg i.v., the thromboxane A2 antagonist group (n = 12) receiving continuous intravenous infusion of ONO-3708 1 microgram/kg/min, the lipoxygenase inhibitor group (n = 11) receiving AA-861 3 mg/kg i.v., the peptidoleukotriene antagonist group (n = 11) receiving continuous intravenous infusion of ONO-1078 1 microgram/kg/min and the vehicle control group (n = 15). Except for ONO-3708, all the other drugs reduced the infarct size (RS-5186: 26.3 +/- 2.4% of risk area (mean +/- SEM), AA-861: 21.8 +/- 1.3%, ONO-1078: 22.5 +/- 4.4% vs control: 54.0 +/- 6.4%, p less than 0.01 respectively) as well as reducing the area of gross myocardial hemorrhage (RS-5186: 3.9 +/- 2.6% of infarct size, AA-861: 5.1 +/- 2.4%, ONO-1078: 5.2 +/- 2.5% vs control: 22.3 +/- 3.9%, p less than 0.01 respectively). RS-5186 and AA-861 reduced the intensity of polymorphonuclear leukocyte infiltration into the infarcted area, however, neither ONO-3708 nor ONO-1078 had any significant influence.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arrhythmias, Cardiac; Benzoquinones; Cardiomyopathies; Chromones; Coronary Disease; Dogs; Hemorrhage; Lipoxygenase Inhibitors; Male; Myocardial Infarction; Myocardium; Neutrophils; Quinones; SRS-A; Thiophenes; Thromboxane A2; Thromboxane-A Synthase

Effects of the administration of a thromboxane A2 (TXA2) analogue (STA2), a leukotriene C4 (LTC4), and a leukotriene D4 (LTD4) on regional myocardial blood flow (RMBF) and hemodynamics were studied in anesthetized, open-chest dogs. The blocking ability of a recently synthesized TXA2 selective antagonist, ONO-3708, and a peptidoleukotriene-selective antagonist, ONO-1078, was also investigated. RMBF was measured continuously in three areas: the left anterior descending coronary artery (LAD) area, the circumflex artery (Cx) area, and the area between LAD and Cx. STA2, LTC4, and LTD4 caused a significant dose-dependent reduction of the RMBF in the LAD area. The peak percentage decrease in RMBF followed by a 10 micrograms dose of STA2, 1 micrograms dose of LTC4, and 1 micrograms dose of LTD4 is 38.6% +/- 3.0%, 39.0% +/- 3.1%, and 36.2% +/- 2.4%, respectively. ED50 for the action of LTC4, LTD4, and STA2 on RMBF is 3, 3, and 50 micrograms, respectively. Pretreatment with the newly developed TXA2 antagonist, ONO-3708 (1 micrograms/kg/min for 10 min), completely inhibited the RMBF reduction induced by STA2 (10 micrograms). Pretreatment with the peptidoleukotriene antagonist, ONO-1078 (1 mg), inhibited the RMBF reduction induced by LTC4 or LTD4 (0.3-3 micrograms). Following pretreatment with a 1 mg dose of ONO-1078, the peak percentage decrease of RMBF caused by a 1 micrograms dose of LTC4 and LTD4 was reduced to 21.1% +/- 2.3% and 19.8% +/- 3.1%, respectively. However, the LTC4 (1 micrograms)-induced reduction of the RMBF was not affected by pretreatment with a TXA2 antagonist, ONO-3708, or an inhibitor of the endogenous production of TXA2, OKY-046.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Flow Velocity; Chromones; Coronary Circulation; Coronary Disease; Dogs; Male; Methacrylates; SRS-A; Thromboxane A2; Thromboxane-A Synthase

Topics: Acrylates; Animals; Coronary Disease; Dogs; In Vitro Techniques; Methacrylates; Mitochondria, Heart; Oxygen Consumption; Thromboxane A2; Thromboxane-A Synthase