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RECEPTORS AND SIGNALING PATHWAYS

Selective estrogen receptor- and estrogen receptor-β agonists rapidly decrease pulmonary artery vasoconstriction by a nitric oxide-dependent mechanism

¹Departments of Surgery and ²Medicine, and ³Cellular and Integrative Physiology, and ⁴Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana

Submitted 5 August 2008 ; accepted in final form 25 September 2008

Both endogenous and exogenous estrogen decrease pulmonary artery (PA) vasoconstriction. Whether these effects are mediated via estrogen receptor (ER)- or ER-β, and whether the contribution of ERs is stimulus-dependent, remains unknown. We hypothesized that administration of the selective ER- agonist propylpyrazole triol (PPT) and/or the selective ER-β agonist diarylpropiolnitrile (DPN) rapidly decreases PA vasoconstriction induced by pharmacologic and hypoxic stimuli via a nitric oxide (NO)-dependent mechanism. PA rings (n = 3–10/group) from adult male Sprague-Dawley rats were suspended in physiologic organ baths. Force displacement was measured. Vasoconstrictor responses to phenylephrine (10^–8M – 10^–5M) and hypoxia (PO₂ 35–45 mmHg) were determined. Endothelium-dependent and -independent vasorelaxation were measured by generating dose-response curves to acetylcholine (10^–8M – 10^–4M) and sodium nitroprusside (10^–9M – 10^–5M). PPT or DPN (10^–9M – 5 x 10^–5M) were added to the organ bath in the presence and absence of the NO-synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) (10^–4M). Selective ER- activation (PPT, 5 x 10^–5M) rapidly (<20 min) decreased phenylephrine-induced vasoconstriction. This effect, as well as PPT's effects on endothelium-dependent vasorelaxation, were neutralized by L-NAME. In contrast, selective ER-β activation (DPN, 5 x 10^–5M) rapidly decreased phase II of hypoxic pulmonary vasoconstriction (HPV). L-NAME eliminated this phenomenon. Lower PPT or DPN concentrations were less effective. We conclude that both ER- and ER-β decrease PA vasoconstriction. The immediate onset of effect suggests a nongenomic mechanism. The contribution of specific ERs appears to be stimulus specific, with ER- primarily modulating phenylephrine-induced vasoconstriction, and ER-β inhibiting HPV. NO inhibition eliminates these effects, suggesting a central role for NO in mediating the pulmonary vascular effects of both ER- and ER-β.

propylpyrazole triol; diarylpropiolnitrile; phenylephrine; hypoxic pulmonary vasoconstriction; nongenomic effects

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