DIFFERENTIAL-EFFECTS OF SULMAZOLE (AR-L 115 BS) ON CONTRACTILE-FORCE AND CYCLIC-AMP LEVELS IN CANINE VENTRICULAR MUSCLE - COMPARISON WITH MDL-17,043

  • 1 January 1985
    • journal article
    • research article
    • Vol. 234  (1) , 267-273
Abstract
MDL-17043 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 (10-5-10-3 M) in the isolated canine ventricular trabeculae in the prsence of pindolol (3 .times. 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-17043 in a concentration-dependent manner up to the highest concentrations tested (10-3 M). AR-L-115-BS shortened these times in concentrations of 3 .times. 10-4 M and lower, but prolonged them in higher concentrations. The positive inotropic effects of MDL-17043 and AR-L-115-BS were associated with increases in the cAMP levels of the muscles. The time course of the increase in cAMP levels differed for the 2 drugs. The elevation in cAMP and the positive inotropic effect produced by MDL-17043 followed a similar time course. The rise in the cAMP 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-17043 into a negative intropic effect, but did not alter the positive inotropic effect of 10-3 M AR-L-115-BS. The concentration-response curve for the inotropic effect of MDL-17043 was shifted markedly to the right and downward in the presence of carbachol, whereas only the lower part of the curve for AR-L-115-BS was shifted to the right by carbachol. The elevation of cAMP is apparently centrally involved in the positive inotropic effect of MDL-17043, but much less so in that of AR-L-115-BS. In higher concentrations (> 3 .times. 10-4 M), AR-L-115-BS produces an additional action that is apparently unrelated to intracellular cAMP in the canine ventricular muscle.

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