1. ¹Institute of Pharmacology, School of Medicine, University of Messina, Messina, Italy
2. ²Department of Internal Medicine, School of Medicine, University of Messina, Messina, Italy
3. ³Institute of Plastic Surgery, School of Medicine, University of Messina, Messina, Italy
4. ⁴Institute of Gynecology, School of Medicine, University of Messina, Messina, Italy
5. ⁵Departments of Physiology and Pharmacology, School of Biological Sciences, University of Messina, Messina, Italy

Correspondence: Dr. Domenica Altavilla, Institute of Pharmacology, School of Medicine, University of Messina, Via C. Valeria, Policlinico Gazzi Torre Biologica 5 Piano, 98125 Messina, Italy. E-mail: daltavilla@unime.it

Received 30 June 2000.

Abstract

It has been shown recently that -zearalenol, a resorcyclic acid lactone, prevents bone loss in a rat model of postmenopausal bone loss. We have therefore investigated the effects of this phytoestrogen on endothelial dysfunction induced by estrogen deficiency in rats. Female mature Sprague-Dawley rats underwent a bilateral oophorectomy (OVX rats). Sham-operated animals (sham OVX rats) were used as controls. Three weeks after surgery, animals were randomized to the following treatments: -zearalenol (1 mg/kg/day, im, for 4 weeks), 17-estradiol (20 g/kg/day, im, for 4 weeks), or their vehicle (100 l, im, of cottonseed oil). Two other groups of rats were treated with -zearalenol or 17-estradiol plus the pure estrogen receptor antagonist ICI 182780 (2.5 mg/kg/day, im, for 4 weeks). Mean arterial blood pressure (MAP), heart rate (HR), total plasma cholesterol, plasma estradiol, and plasma -zearalenol were studied. We also investigated endothelial-dependent (acetylcholine, 10 nm to 10 m) and endothelial-independent (sodium nitroprusside, 15 nm to 30 nm) relaxation of aortic rings, as well as N(G)-methyl-l-arginine (L-NMA: 10 to 100 m)–induced vasoconstriction and calcium-dependent nitric oxide synthase (cNOS) activity in homogenates of lungs taken from both sham OVX rats and OVX rats. Untreated OVX rats had, compared with sham OVX animals, unchanged body weight, MAP, HR, and plasma cholesterol. In contrast oophorectomy reduced plasma estradiol levels (OVX, 2 0.5 pg/ml; sham OVX, 35 6 pg/ml), impaired endothelial-dependent relaxation and blunted L-NMA–induced contraction (L-NMA 100 m: sham 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. Treatment with -zearalenol or with 17-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 data suggest that -zearalenol improves endothelial-dependent relaxation in OVX rats through an estrogen receptor–mediated effect.