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Vol. 283, Issue 1, 116-122, 1997

Estrogen and Selective Estrogen Receptor Modulator LY117018 Enhance Release of Nitric Oxide in Rat Aorta1

Roshanak Rahimian, Ismail Laher, Gregory Dube and Cornelis van Breemen

Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada, V6T 1Z3 (R.R., I.L., C. van B.), and Eli Lilly Research Laboratories, Indianapolis, Indiana (G.D.)

We report on the modulatory effects of chronic subcutaneous or oral estrogen and LY117018, a selective estrogen receptor modulator, on the release of nitric oxide in rings of rat aorta studied under isometric conditions. Dilator responses to acetylcholine (ACh; 10-8 to 10-5 M) were obtained in phenylephrine (PE; 2 µM)-contracted aorta, and constrictor dose-response curves to PE (10-8 to 10-5 M) were generated before and after pretreatment with Nomega -nitro-L-arginine methyl ester (L-NAME; 200 µM), an inhibitor of nitric oxide synthase. Tissue segments were obtained from five groups of rats implanted with a subcutaneous pellet delivery system for 21 days: (1) male, (2) sham-operated placebo-treated female, (3) ovariectomized placebo-treated, (4) ovariectomized, 17beta -estradiol treated (0.5 mg/pellet) and (5) ovariectomized, progesterone (15 mg/pellet) and 17beta -estradiol (0.5 mg/pellet)-treated. Aortic rings from sham rats and ovariectomized rats receiving estrogen relaxed more to ACh (10-6 to 10-5 M) than did the rings from ovariectomized, progesterone plus estrogen-treated and male rats (P < .05). They were also characterized by a greater potentiation of the PE responses after L-NAME compared with male, progesterone plus estrogen-treated and ovariectomized rats (P < .05) and a similar sensitivity to PE. In addition, ACh-induced relaxation and L-NAME-induced potentiation of PE contractions in aortic rings from rats dosed orally with LY117018 were similar to responses of aortic rings from rats dosed orally with estrogen. These results demonstrate that chronically administered estrogen and LY117018 enhance the release of nitric oxide from endothelium in rat aortic rings.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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