The phytoestrogen alpha-zearalenol reverses endothelial dysfunction induced by oophorectomy in rats

It has been shown recently that alpha -zearalenol, a resorcyclic acid lacto ne, prevents bone loss in a rat model of postmenopausal bone loss. We have therefore investigated the effects of this phytoestrogen on endothelial dys function induced by estrogen deficiency in rats. Female mature Sprague-Dawl ey rats underwent a bilateral oophorectomy (OVX rats). Sham-operated animal s (sham OVX rats) were used as controls. Three weeks after surgery, animals were randomized to the following treatments: a-zearalenol (1 mg/kg/day, im , for 4 weeks), 17 beta -estradiol (20 mug/kg/day, im, for 4 weeks), or the ir vehicle (100 mul, im, of cottonseed oil). Two other groups of rats were treated with alpha -zearalenol or 17 beta -estradiol plus the pure estrogen receptor antagonist ICI 182780 (2.5 mg/kg/day, im, for 4 weeks). Mean arte rial blood pressure (MAP), heart rate (HR), total plasma cholesterol, plasm a estradiol, and plasma a-zearalenol were studied. We also investigated end othelial-dependent (acetylcholine, 10 nM to 10 muM) and endothelial-indepen dent (sodium nitroprusside, 15 nM to 30 nM) relaxation of aortic rings, as well as N(G)-methyl-L-arginine (L-NMA: 10 to 100 muM)-induced vasoconstrict ion and calcium-dependent nitric oxide synthase (cNOS) activity in homogena tes of lungs taken from both sham OVX rats and OVX rats. Untreated OVX rats had, compared with sham OVX animals, unchanged body weight. MAP, HP, and p lasma cholesterol, In contrast oophorectomy reduced plasma estradiol levels (OVX, 2 +/- 0.5 pg/ml; sham OVX, 35 +/- 6 pg/ml), impaired endothelial-dep endent relaxation and blunted L-NMA-induced contraction (L-NMA 100 muM: sha m OVX, 2.7 +/- 0.3 g/mg tissue; OVX, 1.3 +/- 0.1 g/mg tissue). Moreover OVX rats showed a reduced calcium-dependent NO synthase (cNOS) activity. Treat ment with a-zearalenol or with 17 beta -estradiol reverted the endothelial dysfunction and increased cNOS activity in lung homogenates. These effects were abolished by the pure estrogen receptor antagonist ICI 182780. Our dat a suggest that a-zearalenol improves endothelial-dependent relaxation in OV X rats through an estrogen receptor-mediated effect.