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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

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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.

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Authors and Affiliations

  1. The 2nd Department of Internal Medicine, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, 466, Nagoya, Japan

    Toshio Torii, Yukio Toki, Nobuyuki Hieda, Yoshinobu Ito, Kenji Okumura, Hidekazu Hashimoto, Takayuki Ito M.D., Kouichi Ogawa & Tatsuo Satake

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  1. Toshio Torii
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  2. Yukio Toki
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  3. Nobuyuki Hieda
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  4. Yoshinobu Ito
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  5. Kenji Okumura
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  6. Hidekazu Hashimoto
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  7. Takayuki Ito M.D.
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  8. Kouichi Ogawa
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Torii, T., Toki, Y., Hieda, N. et al. 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. Heart Vessels 4, 104–111 (1988). https://doi.org/10.1007/BF02058997

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  • DOI: https://doi.org/10.1007/BF02058997

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