The role of cyclic AMP and the dihydropyridine-sensitive channels on the mechanism of action of milrinone (Corotrope).

Milrinone (Corotrope) increased cyclic AMP levels in dog guinea pig and rat cardiac muscle. A correlation between the increase in contractile force and cyclic AMP levels in dog ventricular trabeculae was obtained when measurements were made 60-70 s after the addition of milrinone. When cyclic AMP levels were determined at the time of maximal contractile response, only concentrations of milrinone 200-300 times the inotropic dose had any effects in elevating cyclic nucleotide levels. In dog Purkinje tissue and rat cardiac muscle, milrinone had minimal or no effects on contractile force but increased cardiac cyclic AMP levels. Sequential doses of milrinone to perfused guinea pig hearts resulted in severe tachyphylaxis to the inotropic activity of milrinone. However, under these conditions, milrinone was found to elevate cardiac cyclic AMP upon each administration. Furthermore, in this preparation, cross-tachyphylaxis between Bay K 8644 and milrinone was demonstrated. The mechanism of action of Bay K 8644, which acts on sarcolemmal Ca2+, is not mediated by increases in cyclic AMP. Following development of tachyphylaxis to Bay K 8644, in the guinea pig hearts, addition of milrinone results in no increases in contractile force but a significant increase in cyclic AMP levels. In all of the instances of tachyphylaxis, isoproterenol increased both contractile force and cyclic AMP. The data are discussed and we put forth the hypothesis that increased cardiac force due to milrinone is in part due to a direct or indirect action on sarcolemmal Ca2+ channels.