CHARACTERIZATION OF THE POSITIVE AND NEGATIVE INOTROPIC EFFECTS OF ACETYLCHOLINE IN THE HUMAN MYOCARDIUM

In the human isolated myocardium, acetylcholine (10(-9) to 10(-3) M) e licited a biphasic inotropic effect (a decrease in the lower and an in crease in the higher concentration range) in atrial and a positive ino tropic 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 ventr icles. Atropine (10(-6) M), but not propranolol(10(-6) M), antagonized both positive and negative inotropic effects of acetylcholine, thus s howing that the responses were mediated by muscarinic acetylcholine re ceptors. The use of subtype selective muscarinic receptor antagonists (10(-7) to 10(-5) M), pirenzepine (M(1) > M(3) > M(2)), AF-DX 116 dihy dro-6H-pyridol[2,3-b][1,4]benzodiazepine-6-one base; M(2) > M(1) > M(3 )) and HHSiD (p-fluorohexahydro-siladifenidol hydrochloride; M(3) grea ter than or equal to M(1) >> M(2)) revealed that the negative inotropi c effect of acetylcholine in atrial as well as the positive inotropic effect in ventricular trabeculae were best antagonized by AF-DX 116 an d not by pirenzepine, suggesting the involvement of the muscarinic M(2 ) receptor subtype, possibly linked to different second messenger syst ems. On the other hand, the positive inotropic effect of acetylcholine (10(-6) to 10(-3) M) in the atrial tissue, observed only in preparati on with depressed contractility, was not effectively antagonized by ei ther AF-DX 116 or HHSiD, but was significantly reduced by pirenzepine. Furthermore, the selective muscarinic M(1), receptor agonist McN-A-34 3 (4-(m-chlorophenylcarbamoyloxy)-2-butynyltrimethyl ammonium chloride ; 10(-9) to 10(-3) M), which failed to significantly change the baseli ne 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 piren zepine (10(-5) M). These data show that, besides the muscarinic M(2) r eceptor mediating both negative (atria) and positive (ventricle) inotr opic effects, muscarinic M(1) receptors, capable of reversing depresse d atrial contractility, are present in the human heart.