Soy isoflavones improve endothelial function in spontaneously hypertensive rats in an estrogen-independent manner:: Role of nitric-oxide synthase, superoxide, and cyclooxygenase metabolites

The aim of this study was to analyze the effects of the isoflavones genistein and daidzein, and the mammalian estrogen 17 beta-estradiol on endothelial function in isolated aortic rings from male spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Relaxation to acetylcholine on precontracted rings was impaired and endothelium-dependent contraction to acetylcholine in aortic rings was increased in SHR compared with WKY. Aortic NADPH-stimulated O-2(-) release and prostaglandin (PG)H-2 production evoked by acetylcholine were increased, whereas nitric-oxide synthase activity was reduced in SHR versus WKY. Genistein, daidzein, or 17 beta-estradiol enhanced the relaxant response to acetylcholine and decreased the endothelium-dependent vasoconstrictor responses to acetylcholine in SHR, but not in WKY, and these effects were not modified by the estrogen receptor antagonist ICI 182,780 (7 alpha,17 beta-[9[(4,4,5,5,5-pentafluoropentyl)-sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol). Moreover, isoflavones enhanced nitric-oxide (NO) synthase activity and inhibited NADPH-stimulated O-2(-) roduction and endothelial release of PGH(2). The contractions induced by the TP receptor agonist U46619 (9,11-dideoxy-11 alpha,9 alpha-epoxymethanoprostaglandin F-2 alpha) in denuded aortic rings were inhibited by genistein, daidzein, and 17 beta-estradiol in both strains. In conclusion, the isoflavones genistein and daidzein and 17 beta-estradiol restore endothelial function in male SHR through estrogen receptor-independent mechanisms. Increased NO production and protection of NO from O-2(-)-driven inactivation might be involved in the improvement of vascular relaxation to acetylcholine in aortic rings from SHR. Moreover, isoflavones and 17 beta-estradiol inhibited aortic endothelium-dependent contraction to acetylcholine in SHR by reducing the endothelial PGH(2) release and its vasoconstrictor response.