POSITIVE INOTROPIC EFFECT OF AMRINONE IN RELATION TO CYCLIC NUCLEOTIDE-METABOLISM IN THE CANINE VENTRICULAR MUSCLE

Abstract

Experiments were carried out in the canine isolated right ventricular muscle to study the positive inotropic effect of amrinone in relation to the cAMP and cGMP metabolism. The positive inotropic effect on amrinone was accompanied by accumulation of cAMP in the tissue: the cAMP level was elevated in a similar time course to that of the increase in force of contraction and in a concentration-dependent manner in the presence of a .beta.-adrenoceptor blocking agent pindolol (3 .times. 10-8 M). An excellent correlation was found between the force of contraction and cAMP level in the presence of amrinone; the relationship was similar to that obtained previously with papaverine, a cAMP phosphodiesterase inhibitor. The cGMP level determined simultaneously was not changed by amrinone. The amrinone-induced increases in force of contraction and cAMP level were markedly depressed by carbachol (3 .times. 10-6 M); the relationship between the force of contraction and cAMP level in the presence of amrinone was not changed by carbachol. Amrinone inhibited the cAMP phosphodiesterase purified from the canine right ventricular muscle and enhanced the positive inotropic effect of isoproterenol. Amrinone shortened the time required for relaxation of a single contraction to the same extent as isoproterenol and cAMP phosphodiesterase inhibitors such as 1-methyl-3-isobutylxanthine and papaverine. Evidently, the change in cAMP metabolism is involved in the positive inotropic effect of amrinone on the canine ventricular muscle.