Contribution of endothelin to the coronary vasoconstriction in the isolated rat heart induced by nitric oxide synthase inhibition

The possible involvement of endothelin-1 (ET-1) and angiotensin II in the coronary vasoconstriction induced by nitric oxide synthase (NOS) inhibition was investigated in isolated Langendorff-perfused rat hearts. Fifteen minutes of perfusion with the NOS inhibitor N ^G-nitro-L -arginine (L -NNA, 0.1 mM ) reduced coronary flow by 31%. Pre-treatment with the non-selective ET_A/ET_B receptor antagonist bosentan (1 and 10 μM ) attenuated this reduction in coronary flow to 16% (P < 0.05) and 8% (P < 0.01), respectively. The selective ET_A receptor antagonist BQ-123 (1 μM ) induced a similar inhibitory action, whereas the selective ET_B receptor antagonist BQ-788 and the angiotensin II type 1 receptor antagonist candesartan did not affect the vasoconstrictor response to L -NNA. In addition, bosentan administered after 15 min of L -NNA perfusion reversed the L -NNA-induced reduction in coronary flow in a dose-dependent manner. The high concentration of bosentan (10 μM ) increased the basal coronary flow by 17%, while the lower concentration of bosentan, BQ-123, BQ-788 and candesartan did not affect basal coronary flow. Bosentan (10 μM ) increased the level of ET-like immunoreactivity (-LI) in the coronary effluent twofold. L -NNA did not affect ET-LI level. These results indicate that ET-1 contributes to the coronary vasoconstrictor effect of L -NNA in the isolated rat heart, and that this action of ET-1 is mediated through ET_A receptor activation. Angiotensin II does not seem to contribute to L -NNA-induced vasoconstriction under the present condition.