The effects of amrinone and related drugs on intracellular calcium in isolated mammalian cardiac and vascular smooth muscle.

The effects of amrinone and related agents were studied in mammalian cardiac and vascular smooth muscle preparations loaded intracellularly with aequorin, a bioluminescent calcium indicator that emits light when it combines with Ca++. In cat papillary muscles, the effects of amrinone 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 Ca++, were consistent with reports that, in positive inotropic doses, the predominant action of amrinone is to increase intracellular concentrations of cyclic AMP. However, amrinone also produced dose-related caffeine-like effects on the aequorin light signal, suggesting additional subcellular actions. The positive inotropic effects of amrinone were most pronounced at low frequencies of stimulation (0.01 to 0.25 Hz) and were nearly obliterated at more physiologic heart rates (0.5 to 1.25 Hz). Toxic doses of amrinone were associated with development of a Ca++-overload state characterized by the presence of afterglimmers, aftercontractions, and arrhythmias. Amrinone's relaxant effect on ferret aortic and portal vein strips was associated with a corresponding decrease in intracellular Ca++ levels, and minimally effective relaxant doses were 10 to 100 times lower than positive inotropic doses reported for ferret heart. The vascular effects of amrinone were different from other agents known to increase intracellular cyclic AMP concentrations, suggesting multiple subcellular actions.