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Department of Obstetrics and Gynecology, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0526
Estrogen is believed to protect
postmenopausal women from coronary vascular disease, in part by
increasing production of nitric oxide (NO). In this study, we
investigated the possibility that transcriptional activation of
inducible NO synthase (iNOS) is responsible for a component of the
estrogen-induced increase in coronary blood flow. Twenty-two ewes were
instrumented with Doppler flow probes on their left circumflex coronary
and pulmonary arteries. Nine ewes received 17
-estradiol (1 µg/kg),
and the coronary vascular response was followed for 16 h.
Estradiol significantly increased coronary blood flow by 22 ± 4%
over baseline and the peak response occurred at 2 h
(P < 0.01). To examine the effect of estrogen on NOS
expression in the ovine coronary artery, 17 noninstrumented animals
were killed 2 h after administration of estradiol or vehicle. Coronary arteries were analyzed for ovine iNOS and endothelial NOS
(eNOS) expression by semiquantitative RT-PCR. PCR primers were based on
partial cDNA clones for ovine eNOS and iNOS isolated as part of this
study. The expression of iNOS was significantly increased (27-fold) by
the administration of estradiol, whereas the expression of eNOS was
much weaker (2-fold). To confirm these effects in vivo, additional
instrumented animals received either the estrogen receptor (ER)
antagonist ICI-182,780 (n = 5), the iNOS antagonist
dexamethasone (n = 5), or pyrrolidine dithiocarbamic acid, an inhibitor of nuclear factor-
B (n = 5). All
three antagonists inhibited estrogen-induced increases in coronary
blood flow and increases in cardiac output by over 85%. These results
strongly support the hypothesis that 17-estradiol increases coronary
blood flow in the unanesthetized nonpregnant ewe via an ER-dependent mechanism that results in an increase in both eNOS and iNOS expression.
nitric oxide synthase; blood flow; hormone; coronary disease
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