title: Endothelium-Independent Relaxation of Vascular Smooth Muscle by 17beta-Estradiol.
abstract: BACKGROUND: Estrogens directly dilate arteries, and this acute relaxation of vascular smooth muscle (VSM) may contribute to the cardioprotective effect of this important hormone. However, the mechanism by which estrogens relax VSM is not clear. METHODS AND RESULTS: Based on observations in isolated smooth muscle cells, we hypothesized that 17beta-estradiol (E(2)) causes dilation through receptor-mediated activation of K(+) channels in VSM cells. To test this hypothesis, E(2)-relaxation was studied in arteries from male Sprague-Dawley rats. We observed that the estrogen receptor antagonist, tamoxifen (3 µmol) attenuated E(2) relaxation, suggesting that at least a portion of the relaxation depends on activation of E(2) receptors. The nitric oxide synthase inhibitor, Nomega-nitro-larginine (100 µmol) did not affect E(2) relaxation in either denuded or endothelium-intact arterial strips. Furthermore, inhibition of guanylyl cyclase with LY83583 (10 µmol) had no effect on the relaxation, suggesting that nitric oxide does not contribute to this relaxation. Vascular segments contracted with 90 mmol KCl to disrupt the K(+) gradient had a similar E(2) relaxation does not require K(+)-channel activation. Finally, E(2) pretreatment inhibited contraction of arterial segments depleted of intracellular calcium but in the presence of extracellular calcium. However, E(2) did not affect contraction of strips in calcium-free solution. CONCLUSIONS: These final experiments suggest that E(2) inhibits Ca(2+) influx but not intracellular calcium release. Together, these studies establish that E(2) causes receptor-mediated relaxation of peripheral resistance arteries through inhibition of calcium entry independent of nitric oxide production, guanylyl cyclase stimulation, and K(+)-channel activation.
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA
authors.initials: RJ
authors.lastname: Gonzales
authors.initials: NL
authors.lastname: Kanagy