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) i nhibition was investigated in isolated Langendorff-perfused rat hearts . Fifteen minutes of perfusion with the NOS inhibitor N-G-nitro-L-argi nine (L-NNA, 0.1 mM) reduced coronary flow by 31%. Pre-treatment with the non-selective ETA/ETB receptor antagonist bosentan (1 and 10 mu M) attenuated this reduction in coronary flow to 16% (P < 0.05) and 8% ( P < 0.01), respectively. The selective ETA receptor antagonist BQ-123 (1 mu M) induced a similar inhibitory action, whereas the selective ET B receptor antagonist BQ-788 and the angiotensin II type 1 receptor an tagonist candesartan did not affect the vasoconstrictor response to L- NNA. In addition, bosentan administered after 15 min of L-NNA perfusio n reversed the L-NNA-induced reduction in coronary flow in a dose-depe ndent manner. The high concentration of bosentan (10 mu M) increased t he basal coronary flow by 17%, while the lower concentration of bosent an, BQ-123, BQ-788 and candesartan did not affect basal coronary flow. Bosentan (10 mu M) 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 vasocon strictor effect of L-NNA in the isolated rat heart, and that this acti on of ET-1 is mediated through ETA receptor activation. Angiotensin II does not seem to contribute to L-NNA-induced vasoconstriction under t he present condition.