Effects of a new 1,3-thiazole Derivative ZSY-39 on force of contraction and cyclic AMP content in canine ventricular muscle

Abstract

A newly synthesized 1,3-thiazole derivative ZSY-39 increased the force of contraction in a concentration-dependent manner in association with elevation of tissue cyclic AMP levels in the isolated canine ventricular trabeculae electrically driven at 0.5 Hz at 37 degrees C. ZSY-39 shortened the duration of isometric contractions mainly by abbreviation of the relaxation time. The maximal response to and EC50 of ZSY-39 were 0.7 (isoproterenol = 1.0) and 4.6 x 10(-5) M. Bupranolol (3 x 10(-7) M) did not affect the positive inotropic effect of ZSY-39. The time course of increases in the force of contraction induced by ZSY-39 (10(-4) M) coincided with that of cyclic AMP accumulation. The concentration-response curve for the increase in the force of contraction produced by ZSY-39 was superimposable on that of the elevation of cyclic AMP levels. Carbachol (3 x 10(-6) M) shifted the concentration-response curve for the increase in force by ZSY-39 to the right and downward, and decreased the accumulation of cyclic AMP induced by ZSY-39 (10(-4) M). ZSY-39 (10(-5) M) enhanced significantly the positive inotropic effect of isoproterenol. The relationship between the force of contraction and cyclic AMP levels after the administration of ZSY-39 was not modified by the addition of carbachol or isoproterenol. These findings indicate that cyclic AMP plays an important role in the positive inotropic effect of ZSY-39 on canine ventricular muscle.

Pharmacology of SCH00013: A Novel Ca2+ Sensitizer

“…The cardiotonic agents that possess PDE III inhibitory action enhance the positive inotropic effect of isoproterenol (17,19,32). SCH00013 at 30 ìM shifted the concentrationresponse curves for the positive inotropic effect of isoproterenol to the left in dog and rabbit ventricular myocardium.…”