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 in order to study the positive inotropic effect of amrinone in relation to the cyclic AMP and cyclic GMP metabolism. The positive inotropic effect of amrinone was accompanied by accumulation of cyclic AMP in the tissue: the cyclic AMP 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 X 10(-8) M). An excellent correlation was found between the force of contraction and cyclic AMP level in the presence of amrinone: the relationship was similar to that obtained previously with papaverine, a cyclic AMP phosphodiesterase inhibitor. The cyclic GMP level determined simultaneously was not changed by amrinone. The amrinone-induced increases in force of contraction and cyclic AMP level were markedly depressed by carbachol (3 X 10(-6) M); the relationship between the force of contraction and cyclic AMP level in the presence of amrinone was not changed by carbachol. Amrinone inhibited the cyclic AMP 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 cyclic AMP phosphodiesterase inhibitors such as 1-methyl-3-isobutylxanthine and papaverine. These results altogether strongly suggest that the change in cyclic AMP metabolism is involved in the positive inotropic effect of amrinone on the canine ventricular muscle.