Inhibitory effects of TAK-044 on endothelin induced vasoconstriction in various canine arteries and porcine coronary arteries: a comparison with selective ETA and ETB receptor antagonists.

Abstract

1. The inhibitory effects of the endothelin (ET) receptor antagonist, TAK-044, on ET-induced vasoconstriction in various canine arteries and porcine coronary arteries were studied and were compared to those of selective ETA and ETB receptor antagonists. 2. ET-1 (0.1 nM-0.3 microM) caused vasoconstriction in canine coronary, femoral, renal, mesenteric and basilar arteries, and the strongest responses were obtained in coronary and basilar arteries. TAK-044 (10 nM, 100 nM) inhibited this ET-1-induced vasoconstriction except in the case of mesenteric arteries. The strongest inhibitory effects were obtained in coronary arteries; an EC50 value for ET-1 was 5.2 +/- 0.77 nM (n = 12) in the control and 24 +/- 3.8 nM (n = 4) in the presence of TAK-044 at 10 nM. BQ-123 (1 microM) inhibited the vasoconstriction in coronary and femoral arteries but did not in renal, mesenteric or basilar arteries. 3. TAK-044 (10-100 nM) inhibited the ET-1-induced vasoconstriction in porcine coronary arteries to a degree similar to that in canine coronary arteries. In contrast, BQ-123 (10 microM) did not inhibit the contraction completely, and a BQ-123-insensitive component was identified. Although BQ-788 (1 microM) did not modify the concentration-response curve at all, it abolished the BQ-123-insensitive component when applied together with BQ-123 (10 microM). 4. Sarafotoxin S6c (10 pM-30 nM) caused vasoconstriction in porcine coronary arteries with the maximum amplitude of the contraction being 39% of that with ET-1. Both TAK-044 (10 nM, 100 nM) and BQ-788 (1 microM) inhibited this vasoconstriction, while BQ-123 (3 microM, 10 microM) did not. 5. Vasoconstriction induced by ET-3 (0.1 nM-0.3 microM) in porcine coronary arteries showed a concentration-response curve with two distinct phases in contrast to that seen with sarafotoxin S6c. TAK-044 (0.3 nM-10 nM) inhibited both phases in a concentration-dependent manner. BQ-123 (1 microM, 3 microM) inhibited only the second phase, while BQ-788 (1 microM) inhibited the first phase. 6. We concluded that the inhibitory effects of TAK-044 on ET-1-induced vasoconstriction were the strongest in coronary arteries among the canine arteries examined. In addition, we showed that both ETA and ETB receptors mediate vasoconstriction in porcine coronary arteries and TAK-044 inhibits the vasoconstriction mediated by both of these receptors.