Novel stimulatory actions of the phytoestrogen genistein: effects on the gain of cardiac excitation-contraction coupling.
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.
Liew
Reginald
R
Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College, Dovehouse St., London SW3 6LY, UK. r.liew@imperial.ac.uk
Macleod
Kenneth T
KT
Collins
Peter
P
D008841:Actin Cytoskeleton / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004553:Electric Conductivity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D019833:Genistein / Q000494:pharmacology*; D007529:Isoflavones; D008954:Models, Biological; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D048789:Phytoestrogens; D028321:Plant Preparations; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D004968:Estrogens, Non-Steroidal; D007529:Isoflavones; D048789:Phytoestrogens; D028321:Plant Preparations; D019831:Sodium-Calcium Exchanger; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D002118:Calcium