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Abstract The effect of several recently synthetized cardiotonic agents on a variety of key metabolic processes involved in regulating calcium homeostasis in the cardiac cell was evaluated in an effort to determine the mechanism of action of these compounds. The agents examined were amrinone, WIN 47,203, AR‐L 57, AR‐L 115 (vardax), carbazeran, and RMI 82,249. The results of this study indicate that amrinone and vardax, at concentrations that stimulate myocardial contractility, have no effect on calcium transport, uptake or EGTA‐induced calcium release from isolated sarcoplasmic reticulum vesicles, or on mitochondrial calcium transport or uptake. Amrinone, vardax, and RMI 82,249 also have no effect on mitochondrial respiration. AR‐L 57 and vardax, but not amrinone, WIN 47,203, or carbazeran, inhibit cardiac Na + , K + ‐ATPase activity (IC50 = 140 μM and approximately 1,000 μM, respectively). All of the agents examined inhibit phosphodiesterase activity; WIN 47,203 and carbazeran are the most potent inhibitors, and amrinone, the least. Vardax, amrinone, and carbazeran also potentiate the inotropic response to the beta‐receptor stimulant isoproterenol, and these three agents, in addition to WIN 47,203, also elevate cyclic AMP levels in isolated rabbit papillary muscles. These results indicate that inhibition of phosphodiesterase activity may represent the cardiotonic mechanism of action of amrinone, WIN 47,203, and carbazeran, and perhaps AR‐L 57 and vardax as well. Further studies are required to establish the degree to which Na + , K + ‐ATPase inhibition or other actions are also involved in the cardiotonic activity of AR‐L 57 and vardax.
Weishaar et al. (Sat,) studied this question.