title: Acute effects of toremifene on the vasculature of intact and menopause-induced rats.
abstract: Clinical studies have shown that cardiovascular performance in postmenopausal women could be modified by treatment with selective estrogen receptor modulators (SERM). However, the mechanisms by which these drugs act on the cardiovascular system have not been elucidated. This work evaluates the effect of toremifene, a new member of the SERM family, on the vasculature of intact and ovariectomized adult Sprague-Dawley rats. The responsiveness of rings from the thoracic aorta to norepinephrine, potassium chloride, acetylcholine and sodium nitroprusside was assessed before and after 15 min of incubation with 1.0-microM toremifene. Toremifene displaced the concentration-response curve for norepinephrine-induced contractions to the right in both groups of animals. Moreover, the EC(50) values for the curves increased from 154+/-31 to 754+/-162 nM (P<.05) in intact rats and from 88+/-11 to 230+/-71 nM (P<.05) in ovariectomized rats. Toremifene also reduced contractile responses to potassium chloride (10-120 mM), displacing the entire curve to the right in both groups of animals without modifying the EC(50) values. The drug shifted the concentration-response curve for the acetylcholine-induced relaxation to the left and significantly increased E(max) values (18% for ovariectomized rats vs. 16% for controls) without affecting EC(50) values in either group tested. In addition, toremifene potentiated the relaxing responses to physiological doses (0.1-1.0 nM) of sodium nitroprusside in both groups, suggesting a direct effect at the level of the vascular smooth muscle. Acute toremifene incubation increased basal relaxation in aortic rings from both intact and ovariectomized rats. These results suggest that toremifene, by improving the functional status of the endothelium-smooth muscle unit, may have a beneficial effect on the cardiovascular status of menopause-induced rats.
authors.affiliation: Department of Biology, University of Puerto Rico-Rio Piedras, San Juan, Puerto Rico.
authors.forename: Jorge
authors.initials: J
authors.lastname: González-Pérez
authors.forename: María J
authors.initials: MJ
authors.lastname: Crespo
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010052:Ovariectomy; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017312:Toremifene / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D004965:Estrogen Antagonists; D014665:Vasodilator Agents; D009599:Nitroprusside; D011189:Potassium Chloride; D017312:Toremifene; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine