| Summary: | 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. === Medicine, Faculty of === Anesthesiology, Pharmacology and Therapeutics, Department of === Graduate
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