Endothelin-Dependent Tone Limits Acetylcholine-Induced Dilation of Resistance Coronary Vessels After Blockade of NO Formation in Conscious Dogs

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Abstract
Abstract —Nitric oxide (NO) impairs endothelin (ET) formation and/or action in isolated vessels. We hypothesized that ET may magnify the consequences of NO formation blockade on receptor-operated dilation of resistance coronary vessels in conscious dogs. In conscious instrumented dogs, graded intracoronary (IC) doses of acetylcholine (ACh) were delivered before IC administration of N ω -nitro- l -arginine methyl ester (L-NAME), after L-NAME, and after L-NAME plus IC bosentan, an ET A /ET B receptor blocker. Before L-NAME, ACh (100 ng · kg −1 · min −1 ) increased coronary blood flow (CBF) by 43±4% from 47±6 mL · min −1 . After L-NAME, ACh failed to increase CBF (−3±2% from 50±7 mL · min −1 ). CBF responses to ACh were partially restored (+10±2% from 50±7 mL · min −1 , P A (Ro 61-1790) but not ET B (Ro 46-8443) receptors partially restored CBF responses to ACh after L-NAME. Myocardial immunoreactive ET levels in the perfusion territories of the circumflex and left anterior descending coronary arteries did not differ. ET A -dependent tone magnified the inhibitory effects of blockade of NO formation on receptor-operated dilation to ACh in resistance coronary vessels. Presumably, stimulated NO release has an inhibitory action on endogenous ET production and/or action at the level of resistance coronary vessels.