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CARDIOVASCULAR

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

Department of Pharmacology, School of Pharmacy, University of Granada, Granada, Spain (R.V., M.G., I.C.V., M.S., A.Z., J.D.); and Department of Pharmacology, School of Medicine, University Complutense, Madrid, Spain (F.P.-V.)

The aim of this study was to analyze the effects of the isoflavones genistein and daidzein, and the mammalian estrogen 17-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 17-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 (7,17-[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-11,9-epoxymethanoprostaglandin F₂) in denuded aortic rings were inhibited by genistein, daidzein, and 17-estradiol in both strains. In conclusion, the isoflavones genistein and daidzein and 17-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 17-estradiol inhibited aortic endothelium-dependent contraction to acetylcholine in SHR by reducing the endothelial PGH₂ release and its vasoconstrictor response.

Address correspondence to: Dr. Juan Duarte, Departemento de Farmacología, Facultad de Farmacia, Campus de Cartuja, Universidad de Granada, 18071 Granada, Spain. E-mail: jmduarte{at}ugr.es

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