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

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Abstract

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
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume295
Issue number5
DOIs
StatePublished - Nov 2008

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Vasoconstriction
Estrogen Receptors
Pulmonary Artery
Nitric Oxide
Estrogens
NG-Nitroarginine Methyl Ester
Phenylephrine
Baths
Vasodilation
Lung
Endothelium
Nitroprusside
Vasoconstrictor Agents
Nitric Oxide Synthase
Acetylcholine
Blood Vessels
Sprague Dawley Rats
1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

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title = "Selective estrogen receptor-α and estrogen receptor-β agonists rapidly decrease pulmonary artery vasoconstriction by a nitric oxide-dependent mechanism",
abstract = "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.",
keywords = "Diarylpropiolnitrile, Hypoxic pulmonary vasoconstriction, Nongenomic effects, Phenylephrine, Propylpyrazole triol",
author = "Tim Lahm and Crisostomo, {Paul R.} and Markel, {Troy A.} and Meijing Wang and Yue Wang and Jiangning Tan and Meldrum, {Daniel R.}",
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T1 - Selective estrogen receptor-α and estrogen receptor-β agonists rapidly decrease pulmonary artery vasoconstriction by a nitric oxide-dependent mechanism

AU - Lahm, Tim

AU - Crisostomo, Paul R.

AU - Markel, Troy A.

AU - Wang, Meijing

AU - Wang, Yue

AU - Tan, Jiangning

AU - Meldrum, Daniel R.

PY - 2008/11

Y1 - 2008/11

N2 - 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.

AB - 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.

KW - Diarylpropiolnitrile

KW - Hypoxic pulmonary vasoconstriction

KW - Nongenomic effects

KW - Phenylephrine

KW - Propylpyrazole triol

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U2 - 10.1152/ajpregu.90667.2008

DO - 10.1152/ajpregu.90667.2008

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JO - American Journal of Physiology - Renal Physiology

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