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Estrogen receptor modulation : effects on rat aortic endothelia function

University of British Columbia

Studies were performed to characterize the effects of chronic estrogen receptor activation on basal and stimulated nitric oxide release in the male and female ovariectomized Sprague-Dawley (SD) rat. To determine the effects of chronic treatment with oral LY117108, a selective estrogen receptor modulator, on NO release in the aortic endothelium of the ovariectomized rat, dilator responses to acetylcholine were obtained in phenylephrine-precontracted aorta, and phenylephrine concentration-response curves were generated both before and after pretreatment with Nψ-nitro-L-arginine methyl ester (L-NAME). The level of ACh-induced relaxation is a measurement of the amount of receptor-mediated NO release. Since L-NAME is a nitric oxide synthase (NOS) inhibitor, the potentiation of PE contractions after L-NAME incubation is indicative of the amount of basal NO production in the tissue. Treatment with LY117018 caused an increase in both basal and stimulated NO release in the female ovariectomized SD rat. The potentiation of basal NO release increased with the time of LY117018 treatment, reaching a maximal level at three weeks and was not further augmented by longer treatment periods. The dose of LY117018 also affected the level of potentiation of basal NO release. Maximal potentiation of basal NO release occurred with LY117018 doses between 1.0 and 5.0mg/kg/day, inclusive. With doses lower or higher than this range, the effect diminished. LY117018 potentiated stimulated NO release in a dose-dependent manner. This effect was not dependent on the duration of treatment. Chronic subcutaneous 17β-estradiol administration potentiated basal NO release in the male SD rat in a time- and dose-dependent manner, but showed no effect on stimulated NO release. 17β-estradiol increased the sensitivity of the aortic smooth muscle in the male rat to phenylephrine. These results demonstrate that chronic administration of oral LY117018 enhanced basal and stimulated NO release in the ovariectomized rat in a time-and dose- dependent manner. Chronic administration of subcutaneous 17β-estradiol enhanced basal NO release in the male rat in a time- and dose-dependent manner. Because potentiation of NO release has been postulated to be one of the mechanisms underlying estrogen's cardioprotective effect, the results of this study have many potential clinical implications. The enhanced endothelial function caused by LY117018 or 17β-estradiol could be used to protect against many cardiovascular diseases in both men and women.

Thesis/Dissertation

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2009-05-19

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http://hdl.handle.net/2429/7948

Pharmacology and Therapeutics

University of British Columbia

UBCV

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