title: Genistein stimulates myocardial contractility in guinea pigs by different subcellular mechanisms.
abstract: The purpose of this study was to investigate the mechanisms involved in the excitatory effect induced by genistein in isolated guinea pig left ventricular papillary muscles and to determine relationship of genistein action with the tyrosine kinase pathway and phosphatidylinositol 3-kinase (PI3K) activity, the cyclic adenosine 5'-monophosphate (cAMP) signal system and the sarcoplasmic reticulum Ca2+ mobilization. Genistein (1-100 microM) significantly increased contraction of left ventricular papillary muscles from male and female guinea pigs in a concentration-dependent manner and its action had no obvious gender differences. Prior treatment with an L-type Ca2+ channel blocker verapamil hydrochloride, beta-adrenoceptor inhibitors propranolol and atenolol, an inhibitor of Na+-Ca2+ reverse exchanger Kb-r7943 or the blocker of estrogen receptor ICI 182,780 failed to alter the positive inotropic effect induced by genistein in papillary muscles. However, tyrosine phosphatase inhibitor, sodium orthovanadate or a potent phosphotyrosine phosphatase inhibitor bpV (phen) could partly but significantly reduce the stimulatory action of genistein. Interestingly, insulin-like growth factor-1, a known PI3K activator could also decrease the stimulatory action of genistein obviously, but the PI3K inhibitor LY294002 had no significant effect on the stimulatory action of genistein. The excitatory effect of genistein was markedly attenuated not only after treatment with an inhibitor of cAMP synthesis Sq 22536, carbachol or an inhibitor of specific protein kinase A H-89, but also after the inhibition of sarcoplasmic reticulum Ca2+ mobilization by ruthenium red, ryanodine or the inhibitor of sarcoplasmic reticulum Ca2+-ATPase thapsigargin. All these results indicate that the excitatory effects of genistein in papillary muscles are due to the inhibition of tyrosine kinase pathway and PI3K activity, thereby locally activating cAMP signal transduction and facilitating intracellular Ca2+ mobilization, but are not related to the activation of beta-adrenoceptor, the Na+-Ca2+ reverse exchange and the estrogen receptor.
authors.affiliation: Department of Physiology, College of Basic Medicine, Lanzhou University, Lanzhou 730000, PR China. lhof@tom.com
authors.forename: Hongfang
authors.initials: H
authors.lastname: Li
authors.forename: Yingfu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Tian
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Qiu
authors.forename: Jing
authors.initials: J
authors.lastname: Gu
authors.forename: Jinxia
authors.initials: J
authors.lastname: Wu
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D019833:Genistein / Q000494:pharmacology*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
chemical_list: D002118:Calcium; D002316:Cardiotonic Agents; D000242:Cyclic AMP; D019833:Genistein; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases