Endoh_1985_J.Pharmacol.Exp.Ther_234_267

MDL 17,043 [1,3-dihydro-4-methyl-5-[4-(methylthio)-benzoyl]-2H-imidazol-2-one] and AR-L 115 BS [sulmazole, 2-[(2-methoxy-4-methylsulfinyl)phenyl]-1H-imidazo[4,5-b] pyridine] produced substantial positive inotropic effects in a concentration-dependent manner (10(-5) to 10(-3) M) in the isolated canine ventricular trabeculae in the presence of pindolol (3 X 10(-8) M). Both agents exhibited equal potency and intrinsic activity in this preparation. The time to peak tension, relaxation time and total duration of contraction were shortened by MDL 17,043 in a concentration-dependent manner up to the highest concentrations tested (10(-3) M). In contrast, AR-L 115 BS shortened these times in concentrations of 3 X 10(-4) M and lower, but prolonged them in higher concentrations. The positive inotropic effects of MDL 17,043 and AR-L 115 BS were associated with increases in the cyclic AMP levels of the muscles. The time course of the increase in cyclic AMP levels differed for the two drugs. The elevation in cyclic AMP and the positive inotropic effect produced by MDL 17,043 followed a similar time course. By contrast, the rise in the cyclic AMP level became significant only after the positive inotropic effect produced by AR-L 115 BS had reached a steady level. Carbachol, a muscarinic agonist, converted the positive inotropic effect of 10(-3) M MDL 17,043 into a negative inotropic effect, but did not alter the positive inotropic effect of 10(-3) M AR-L 115 BS.(ABSTRACT TRUNCATED AT 250 WORDS)