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

Tim Lahm, Paul R. Crisostomo, Troy A. Markel, Meijing Wang, Yue Wang, Jiangning Tan, Daniel R. Meldrum

Research output: Contribution to journalArticle

43 Scopus citations


Both endogenous and exogenous estrogen decrease pulmonary artery (PA) vasoconstriction. Whether these effects are mediated via estrogen receptor (ER)-α or ER-β, and whether the contribution of ERs is stimulus-dependent, remains unknown. We hypothesized that administration of the selective ER-α 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 × 10-5M) were added to the organ bath in the presence and absence of the NO-synthase inhibitor N ω-nitro-L-arginine methyl ester (L-NAME) (10-4M). Selective ER-α activation (PPT, 5 × 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 × 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-α 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-α 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-α and ER-β.

Original languageEnglish (US)
Pages (from-to)R1486-R1493
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Issue number5
StatePublished - Nov 2008


  • Diarylpropiolnitrile
  • Hypoxic pulmonary vasoconstriction
  • Nongenomic effects
  • Phenylephrine
  • Propylpyrazole triol

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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