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Articles in PresS, published online ahead of print January 11, 2002
J Appl Physiol, 10.1152/jap.00559.2001
Submitted on June 1, 2001
Accepted on December 31, 1969
1 Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
2 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: ebrooks{at}cato.com.
The influence of chronic estradiol treatment on vascular function in obese, insulin-resistant male Zucker rats was assessed. We hypothesized that estradiol administration would improve endothelium-dependent vasodilation and attenuate vasoconstrictor responses commonly observed in rodent models of obesity, hyperlipidemia, and insulin-resistance via an upregulation of NOSIII protein expression. A sham operation or a 21-day release 17ß-estradiol (0.1 mg) pellet implantation was performed in male lean and obese Zucker rats. Maximal contractile responses to phenylephrine (PE) and potassium chloride (KCl) were exaggerated in the untreated obese Zuckers compared to the lean Zuckers, but estrogen treatment significantly attenuated this response in the obese Zuckers. In contrast, estradiol reduced the PE concentration required to evoke 50% of the maximal tension (EC50) in lean and obese rats. This effect was not a result of a cyclooxygenase-dependent factor, because preincubation of the rings with 10-4M indomethacin similarly reduced the contractile response to PE in a subset of LC and LE rats. Endothelium-dependent (acetylcholine, ACh) and -independent vasodilation (sodium nitroprusside, SNP) was determined following precontraction of the aorta with PE (
10-6M). Vasorelaxation to SNP was similar among all groups, but vasorelaxation to ACh was significantly impaired in the obese Zuckers compared to the lean Zuckers. Estradiol improved vasorelaxation in lean and obese Zuckers by decreasing EC50, but impaired function by decreasing maximal vasorelaxation. The shift in EC50 corresponded to an upregulation in NOSIII protein expression in the aorta of the estrogen-treated obese group. In conclusion, estrogen treatment improves vascular reactivity in male insulin-resistant, obese Zucker rats partially via an upregulation of NOSIII protein expression. However, these effects are counteracted by adverse factors, such as hyperlipidemia and potentially a release of an endothelium-derived contractile agent contributing to exaggerated vascular sensitivity to PE.
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