Characterization of the positive and negative inotropic effects of acetylcholine in the human myocardium (original) (raw)

1995, European Journal of Pharmacology

In the human isolated myocardium, acetylcholine (10-9 to 10-3 M) elicited a biphasic inotropic effect (a decrease in the lower and an increase in the higher concentration range) in atrial and a positive inotropic effect in ventricular trabeculae. However, under conditions of raised contractility achieved by exposure to noradrenaline (10-5 M), only negative inotropic effects were observed in both atria and ventricles. Atropine (10-6 M), but not propranolol (10-6 M), antagonized both positive and negative inotropic effects of acetylcholine, thus showing that the responses were mediated by muscarinic acetylcholine receptors. The use of subtype selective muscarinic receptor antagonists (10-7 to 10-5 M), pirenzepine (M 1 > M 3 > M2) , AF-DX 116 (••-({2-[(diethy•amin•)-methy•]-•-piperidy•}acety•)-5•••-dihydr•-6H-pyrid••[2•3-b][••4]benz•diazepine-6-•ne base; M 2 > M 1 > M 3) and HHSiD (p-fluorohexahydro-siladifenidol hydrochloride; M 3 >_ M 1 >> M 2) revealed that the negative inotropic effect of acetylcholine in atrial as well as the positive inotropic effect in ventricular trabeculae were best antagonized by AF-DX 116 and not by pirenzepine, suggesting the involvement of the muscarinic M 2 receptor subtype, possibly linked to different second messenger systems. On the other hand, the positive inotropic effect of acetylcholine (10-6 to 10-3 M) in the atrial tissue, observed only in preparation with depressed contractility, was not effectively antagonized by either AF-DX 116 or HHSiD, but was significantly reduced by pirenzepine. Furthermore, the selective muscarinic M 1 receptor agonist McN-A-343 (4-(m-chlorophenylcarbamoyloxy)-2-butynyltrimethyl ammonium chloride; 10-9 to 10-3 M), which failed to significantly change the baseline contractility in either atrial or ventricular trabeculae, produced a positive inotropic effect in atrial preparations when contractility had been depressed by prior treatment with acetylcholine (10-9 to 10-7 M). This effect of McN-A-343 was effectively antagonized by pirenzepine (10-5 M). These data show that, besides the muscarinic M 2 receptor mediating both negative (atria) and positive (ventricle) inotropic effects, muscarinic M 1 receptors, capable of reversing depressed atrial contractility, are present in the human heart.