Effects of a new thromboxane A2-antagonist (ONO-3708) and a new leukotriene-antagonist (ONO-1078) on thromboxane A2 analogue-, leukotriene C4-, and D4-induced regional myocardial blood flow reduction.

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)