The effects of milrinone and piroximone on intracellular calcium handling in working myocardium from the ferret.

The effects of milrinone and piroximone were compared to those of isoprenaline, dibutyryl adenosine 3':5'-cyclic monophosphate (dibutyryl cyclic AMP), forskolin, isobutylmethylxanthine, increased extracellular calcium [( Ca2+]o) and caffeine in ferret right ventricular papillary muscles that were loaded intracellularly with aequorin, a bioluminescent calcium indicator that emits light when it combines with calcium. The positive inotropic action of each drug, except caffeine, was associated with an increase in the peak amplitude of the aequorin light signal (i.e. intracellular Ca2+ transient) reflecting an increased amount of calcium available for excitation-contraction coupling; the positive inotropic effect of caffeine appears to occur by other mechanisms. The time courses of the aequorin light signal and corresponding tension response were shortened by isoprenaline, forskolin, isobutylmethylxanthine, dibutyryl cyclic AMP, milrinone and piroximone; unchanged by increased [Ca2+]o and prolonged by caffeine, suggesting that the rates of Ca2+ release and uptake by the sarcoplasmic reticulum were respectively increased, unchanged or decreased by these groups of drugs. Relative to changes in [Ca2+]o, the ratio of the peak of the aequorin light signal to the peak of the tension response was increased by isoprenaline, milrinone and piroximone, and decreased by caffeine, indicating that the Ca2+-sensitivity of the myofilaments was respectively decreased, and increased by these drugs. The effects of milrinone and piroximone on the amplitude and time course of the aequorin light signal, as they relate to changes in uptake and release of calcium from the sarcoplasmic reticulum and to changes in the sensitivity of the myofilaments to Ca2+, are consistent with the findings that positive inotropic doses of these agents act by increasing intracellular concentrations of cyclic AMP. Higher doses of milrinone and piroximone produced negative inotropic effects that were characterized by diminution of developed tension but no change or an increase in the amplitude of the aequorin light signal, suggesting a decrease in the sensitivity of the contractile elements to Ca2+. Toxic doses of milrinone, piroximone and isoprenaline were associated with development of a Ca2+-overload state characterized by the presence of after-glimmers, after-contractions and dysrhythmias, and by decreased amplitude of both the aequorin light signal and tension response. The negative inotropic and toxic effects of milrinone and piroximone can be explained only in part by increased intracellular concentrations of cyclic AMP; we suggest that these drugs may have other cardiac actions.