Soy Isoflavones Improve Endothelial Function in Spontaneously Hypertensive Rats in an Estrogen-Independent Manner: Role of Nitric-Oxide Synthase, Superoxide, and Cyclooxygenase Metabolites

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Abstract
The aim of this study was to analyze the effects of the isoflavones genistein and daidzein, and the mammalian estrogen 17β-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 release and prostaglandin (PG)H2 production evoked by acetylcholine were increased, whereas nitric-oxide synthase activity was reduced in SHR versus WKY. Genistein, daidzein, or 17β-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 (7α,17β-[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 roduction and endothelial release of PGH2. The contractions induced by the TP receptor agonist U46619 (9,11-dideoxy-11α,9α-epoxymethanoprostaglandin F2α) in denuded aortic rings were inhibited by genistein, daidzein, and 17β-estradiol in both strains. In conclusion, the isoflavones genistein and daidzein and 17β-estradiol restore endothelial function in male SHR through estrogen receptor-independent mechanisms. Increased NO production and protection of NO from -driven inactivation might be involved in the improvement of vascular relaxation to acetylcholine in aortic rings from SHR. Moreover, isoflavones and 17β-estradiol inhibited aortic endothelium-dependent contraction to acetylcholine in SHR by reducing the endothelial PGH2 release and its vasoconstrictor response.