Inhibitory effect of genistein on agonist-induced modulation of vascular contractility.
The present study was undertaken to determine whether treatment with genistein, the plant-derived estrogen-like compound influences agonist-induced vascular smooth muscle contraction and, if so, to investigate related mechanisms. The measurement of isometric contractions using a computerized data acquisition system was combined with molecular experiments. Genistein completely inhibited KCl-, phorbol ester-, phenylephrine-, fluoride- and thromboxane A(2)-induced contractions. An inactive analogue, daidzein, completely inhibited only fluoride-induced contraction regardless of endothelial function, suggesting some difference between the mechanisms of RhoA/Rho-kinase activators such as fluoride and thromboxane A(2). Furthermore, genistein and daidzein each significantly decreased phosphorylation of MYPT1 at Thr855 had been induced by a thromboxane A(2) mimetic. Interestingly, iberiotoxin, a blocker of large-conductance calcium-activated potassium channels, did not inhibit the relaxation response to genistein or daidzein in denuded aortic rings precontracted with fluoride. In conclusion, genistein or daidzein elicit similar relaxing responses in fluoride-induced contractions, regardless of tyrosine kinase inhibition or endothelial function, and the relaxation caused by genistein or daidzein was not antagonized by large conductance K(Ca)-channel inhibitors in the denuded muscle. This suggests that the RhoA/Rho-kinase pathway rather than K(+)-channels are involved in the genistein-induced vasodilation. In addition, based on molecular and physiological results, only one vasoconstrictor fluoride seems to be a full RhoA/Rho-kinase activator; the others are partial activators.
Je
Hyun Dong
HD
Department of Pharmacology, College of Pharmacy, Catholic University of Daegu, Gyeongsan, 712-702, Korea.
Sohn
Uy Dong
UD
D000818:Animals; D001011:Aorta / Q000187:drug effects*; D015153:Blotting, Western; D002273:Carcinogens / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology*; D007529:Isoflavones / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D048789:Phytoestrogens / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D054645:Protein Phosphatase 1 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012969:Sodium Fluoride / Q000494:pharmacology; D013928:Thromboxane A2 / Q000494:pharmacology; D014118:Toxins, Biological / Q000494:pharmacology; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
D002273:Carcinogens; D002316:Cardiotonic Agents; D007529:Isoflavones; D010455:Peptides; D010703:Phorbol Esters; D048789:Phytoestrogens; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D014118:Toxins, Biological; D010656:Phenylephrine; D013928:Thromboxane A2; C004742:daidzein; D011189:Potassium Chloride; C064719:iberiotoxin; D012969:Sodium Fluoride; D019833:Genistein; C499850:Ppp1r12a protein, rat; D054645:Protein Phosphatase 1; D020742:rhoA GTP-Binding Protein