Novel stimulatory actions of the phytoestrogen genistein: effects on the gain of cardiac excitation-contraction coupling

Abstract

Genistein, a phytoestrogen found abundantly in soy products, is thought to be cardioprotective, partly through its ability to act as a natural Ca2+ channel antagonist. However, the precise nature and significance of such direct cardiac actions remain obscure. We investigated the hypothesis that genistein exerts important additional actions on cardiac excitation-contraction coupling (ECC). Genistein acutely increased cell shortening and the Ca2+ transient in field stimulated guinea-pig ventricular myocytes despite potently inhibiting the L-type Ca2+ current, I(Ca,L). The specific phosphotyrosine phosphatase inhibitor, bpV(phen), diminished the stimulatory effects of genistein on myocyte contractility, suggesting that the mechanism partly involved tyrosine kinase inhibition. Genistein increased sarcoplasmic reticulum (SR) Ca2+ load as measured with a caffeine pulse in Na+-free/ Ca2+-free solution. Furthermore, in the continued presence of caffeine, genistein increased the time constant of decline of the caffeine-induced Ca2+ transient, implying impaired sarcolemmal Na+/Ca2+ exchanger function. Tetanization studies in intact myocytes revealed that 43% of cells exhibited increased myofilament Ca2+ sensitivity in the presence of genistein. These findings demonstrate novel cardiac actions of genistein on the SR Ca2+ load, Na+/Ca2+ exchanger, and myofilament Ca2+ sensitivity, which result in an overall increase in myocyte contractility and consequently the gain of ECC.