Intracoronary Genistein Acutely Increases Coronary Blood Flow in Anesthetized Pigs through β-Adrenergic Mediated Nitric Oxide Release and Estrogenic Receptors

Abstract

Various studies have suggested that the phytoestrogen genistein has beneficial cardioprotective and vascular effects. However, there has been scarce information regarding the primary effect of genistein on coronary blood flow and its mechanisms including estrogen receptors, autonomic nervous system, and nitric oxide (NO). The present study was planned to determine the primary effect of genistein on coronary blood flow and the mechanisms involved. In anesthetized pigs, changes in left anterior descending coronary artery caused by intracoronary infusion of genistein at constant heart rate and arterial pressure were assessed using ultrasound flowmeters. In 25 pigs, genistein infused at 0.075 mg/min increased coronary blood flow by about 16.3%. This response was graded in a further five pigs by increasing the infused dose of the genistein between 0.007 and 0.147 mg/min. In the 25 pigs, blockade of cholinergic receptors (iv atropine; five pigs) and alpha-adrenergic receptors (iv phentolamine; five pigs) did not abolish the coronary response to genistein, whose effects were prevented by blockade of beta(2)-adrenergic receptors (iv butoxamine; five pigs), nitric oxide synthase (intracoronary N(omega)-nitro-L-arginine methyl ester; five pigs) and estrogenic receptors (ERs; ERalpha/ERbeta; intracoronary fulvestrant; five pigs). In porcine aortic endothelial cells, genistein induced the phosphorylation of endothelial nitric oxide synthase and NO production through ERK 1/2, Akt, and p38 MAPK pathways, which was prevented by the concomitant treatment by butoxamine and fulvestrant. In conclusion, genistein primarily caused coronary vasodilation the mechanism of which involved ERalpha/ERbeta and the release of NO through vasodilatory beta(2)-adrenoreceptor effects.

Intracoronary Des-Acyl Ghrelin Acutely Increases Cardiac Perfusion Through a Nitric Oxide-Related Mechanism in Female Anesthetized Pigs

“…Hence, in anesthetized pigs, iv infusion of many agents including ghrelin was able to primarily cause coronary vasoconstriction by inhibiting a vasodilatory ␤-adrenoceptors-mediated effect related to the release of NO (11,46). In addition, the effects of gastrin, secretin and human chorionic gonadotropin on coronary circulation and cardiac function could be prevented by the blockade of ␤-adrenoceptors and NOS (25)(26)(27), whereas intracoronary genistein and melatonin acutely increased coronary blood flow through ␤-adrenergic-mediated NO release (28,29). Finally, the administration of insulin induced a coronary vasoconstriction, which could be considered as the net result of sympathetic ␣-adrenergic activation and increased release of NO (48).…”

Modulation of Oxidative Stress by 17 β-Estradiol and Genistein in Human Hepatic Cell Lines In Vitro

“…The downstream pathway activated by the interaction of estrogens and phytoestrogens with those receptors could lead, among other results, to p38 mitogen activated protein kinases (MAPK) [2, 9, 10] and Akt/phosphatase and tensin homolog activation [10-12]. …”

Cooperative Effects of Q10, Vitamin D₃, and <smlcap>L</smlcap>-Arginine on Cardiac and Endothelial Cells

“…Also, MAP kinases, important mediators of signal transduction from the cell surface to the nucleus, have been found to modulate eNOS activation [48]. Indeed, in PAE cells, ERK and Akt pathways have recently been implicated in the effects of various agents on NO production [35,49]. Data from this study clearly demonstrate that the administration of QLD induced the highest production of NO and acutely increased the phosphorylation of eNOS, Akt, and ERK, which are known to be involved in the intracellular signaling leading to NO production [45,50,51].…”