title: Selective estrogen receptor-alpha and estrogen receptor-beta 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)-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.
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Lahm
authors.forename: Paul R
authors.initials: PR
authors.lastname: Crisostomo
authors.forename: Troy A
authors.initials: TA
authors.lastname: Markel
authors.forename: Meijing
authors.initials: M
authors.lastname: Wang
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Jiangning
authors.initials: J
authors.lastname: Tan
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Meldrum
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists*; D047629:Estrogen Receptor beta / Q000819:agonists*; D000860:Hypoxia / Q000503:physiopathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000494:pharmacology; D010636:Phenols; D010656:Phenylephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D009570:Nitriles; D010636:Phenols; D011422:Propionates; D011720:Pyrazoles; D014662:Vasoconstrictor Agents; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol; D010656:Phenylephrine; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D019331:NG-Nitroarginine Methyl Ester