Influence of nitric oxide synthase inhibition and endothelin-1 receptor blockade on acetylcholine-induced coronary artery contraction in vitro in dilated and ischemic cardiomyopathies

The normal dilatory response to acetylcholine (ACH) is reduced in coronary vessels from patients with dilated cardiomyopathy (DCM) and reversed to a c ontraction in patients with coronary artery disease (CAD) and ischemic card iomyopathy (ICM). This study investigated the influence of nitric oxide syn thase inhibition and endothelin (ET)-1 receptor blockade on the reactivity to ACH of coronary arteries isolated from patients with endstage congestive heart failure (CHF) associated or not with CAD, Small (similar to 400 mum) epicardial right coronary arteries were isolated from explanted hearts of patients undergoing transplantation for DCM or ICM. Segments were mounted o n a wire myograph to record changes in isometric tension. ACH (1 muM) dilat ed pre-contracted vessels from DCM hearts but contracted precontracted vess els from ICM hearts. In the absence of pre-contraction, ACH (10(-9)-3 x 10( -5) M) induced a small contraction of rings from DCM hearts and a larger co ntraction (p < 0.05) of rings from ICM hearts. N-omega-nitro-L-arginine (L- NNA, 100 muM), a NO synthase inhibitor, increased (p < 0.05) sensitivity an d maximal response to ACH of vessels from DCM hearts only. In the presence of L-NNA, blockade of ET, with BQ123 (1 muM) prevented the effects of L-NNA in DCM, whereas blockade of ETA/B receptors with bosentan (10 muM) only re duced vascular sensitivity to ACH without significantly reducing the maxima l contraction to ACH in DCM, The antagonists had no effects in vessels from ICM hearts. AGH, however, induced similar contractions of vessels without endothelium in DCM and ICM. These results suggest that ACH induces a contra ction by stimulating smooth muscle muscarinic receptors. In coronary arteri es isolated from DCM hearts, the contraction is regulated by NO and ET-1, w hereas these factors seem to have little influence in ICM. This suggests th at endothelial muscarinic receptors are either not expressed or uncoupled i n ICM hearts.