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

Summary 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 µg dose of STA₂, 1 µg dose of LTC₄, and 1 µg 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 µg, respectively. Pretreatment with the newly developed TXA₂ antagonist, ONO-3708 (1 µg/kg/min for 10 min), completely inhibited the RMBF reduction induced by STA₂ (10 µg). Pretreatment with the peptidoleukotriene antagonist, ONO-1078 (1 mg), inhibited the RMBF reduction induced by LTC₄ or LTD₄ (0.3–3 µg). Following pretreatment with a 1 mg dose of ONO-1078, the peak percentage decrease of RMBF caused by a 1 µg dose of LTC₄ and LTD₄ was reduced to 21.1%±2.3% and 19.8%±3.1%, respectively. However, the LTC₄ (1 µg)-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. Likewise, the reduction of the RMBF induced by STA₂ (10 µg) was not affected by pretreatment with a leukotriene-antagonist, ONO-1078. These results suggest that the reduction of RMBF induced by TXA₂, LTC₄, and LTD₄ is mediated in vivo through different vascular receptors for each.