Amiloride: effects on myocardial force of contraction, sodium pump and Na+/Ca2+ exchange

The direct effects of amiloride on myocardial contractility were examined in electrically stimulated left atrial muscle of guinea-pig heart. Amiloride (0.3 to 1.5 mM) produced a positive inotropic effect which, at higher concentrations, was followed by a decline in developed tension. These effects were not accompanied by contracture or arrhythmia and were not affected by a combination of phentolamine, nadolol, cimetidine, tripelennamine and atropine. The above concentrations of amiloride prolonged the action potential duration during the development of the positive inotropic effect; however, no further change in the action potential duration was observed during the decline in developed tension caused by high concentrations of amiloride. Myocardial membrane Na,K-ATPase, ouabain-sensitive 86Rb+ uptake and Na+-dependent Ca2+ efflux from sarcolemmal membrane vesicles were all inhibited by amiloride. The positive inotropic effect of the agent is reduced and the negative inotropic action is enhanced in low Na+ solutions, i.e., under conditions likely to favor Ca2+ influx via Na+/Ca2+ exchange. These results suggest that amiloride, under the present conditions, has a complex interaction with cardiac muscle fibers. Amiloride may produce its inotropic effects in guinea-pig atrial muscle by several mechanisms including sodium pump inhibition, Na+/Ca2+ exchange inhibition, prolongation of the action potential duration, and/or actions such as Na+/H+ exchange inhibition which were not directly addressed in this study.