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

Am J Physiol Regul Integr Comp Physiol. 2008 Nov;295(5):R1486-93. doi: 10.1152/ajpregu.90667.2008. Epub 2008 Oct 1.


Both endogenous and exogenous estrogen decrease pulmonary artery (PA) vasoconstriction. Whether these effects are mediated via estrogen receptor (ER)-alpha or ER-beta, and whether the contribution of ERs is stimulus-dependent, remains unknown. We hypothesized that administration of the selective ER-alpha agonist propylpyrazole triol (PPT) and/or the selective ER-beta 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(-8)M - 10(-5)M) and hypoxia (Po(2) 35-45 mmHg) were determined. Endothelium-dependent and -independent vasorelaxation were measured by generating dose-response curves to acetylcholine (10(-8)M - 10(-4)M) and sodium nitroprusside (10(-9)M - 10(-5)M). PPT or DPN (10(-9)M - 5 x 10(-5)M) were added to the organ bath in the presence and absence of the NO-synthase inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME) (10(-4)M). Selective ER-alpha activation (PPT, 5 x 10(-5)M) 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-beta activation (DPN, 5 x 10(-5)M) 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-alpha and ER-beta decrease PA vasoconstriction. The immediate onset of effect suggests a nongenomic mechanism. The contribution of specific ERs appears to be stimulus specific, with ER-alpha primarily modulating phenylephrine-induced vasoconstriction, and ER-beta inhibiting HPV. NO inhibition eliminates these effects, suggesting a central role for NO in mediating the pulmonary vascular effects of both ER-alpha and ER-beta.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Enzyme Inhibitors / pharmacology
  • Estrogen Receptor alpha / agonists*
  • Estrogen Receptor beta / agonists*
  • Hypoxia / physiopathology
  • Male
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide / physiology*
  • Nitric Oxide Synthase Type I / antagonists & inhibitors
  • Nitriles / pharmacology
  • Phenols
  • Phenylephrine / antagonists & inhibitors
  • Phenylephrine / pharmacology
  • Propionates / pharmacology
  • Pulmonary Artery / drug effects*
  • Pyrazoles / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Vasoconstriction / drug effects*
  • Vasoconstrictor Agents / antagonists & inhibitors
  • Vasoconstrictor Agents / pharmacology


  • 2,3-bis(4-hydroxyphenyl)-propionitrile
  • Enzyme Inhibitors
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Nitriles
  • Phenols
  • Propionates
  • Pyrazoles
  • Vasoconstrictor Agents
  • 4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol
  • Phenylephrine
  • Nitric Oxide
  • Nitric Oxide Synthase Type I
  • NG-Nitroarginine Methyl Ester