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 contraction in patients with coronary artery disease (CAD) and ischemic cardiomyopathy (ICM). This study investigated the influence of nitric oxide synthase inhibition and endothelin (ET)-1 receptor blockade on the reactivity to ACH of coronary arteries isolated from patients with end-stage congestive heart failure (CHF) associated or not with CAD. Small (approximately 400 microm) epicardial right coronary arteries were isolated from explanted hearts of patients undergoing transplantation for DCM or ICM. Segments were mounted on a wire myograph to record changes in isometric tension. ACH (1 microM) dilated pre-contracted vessels from DCM hearts but contracted pre-contracted vessels 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 contraction (p < 0.05) of rings from ICM hearts. N(omega)-nitro-L-arginine (L-NNA, 100 microM), a NO synthase inhibitor, increased (p < 0.05) sensitivity and maximal response to ACH of vessels from DCM hearts only. In the presence of L-NNA, blockade of ET(A) with BQ123 (1 microM) prevented the effects of L-NNA in DCM, whereas blockade of ET(A/B) receptors with bosentan (10 microM) only reduced vascular sensitivity to ACH without significantly reducing the maximal contraction to ACH in DCM. The antagonists had no effects in vessels from ICM hearts. ACH, however, induced similar contractions of vessels without endothelium in DCM and ICM. These results suggest that ACH induces a contraction by stimulating smooth muscle muscarinic receptors. In coronary arteries isolated from DCM hearts, the contraction is regulated by NO and ET-1, whereas these factors seem to have little influence in ICM. This suggests that endothelial muscarinic receptors are either not expressed or uncoupled in ICM hearts.