title: beta-adrenergic relaxation in pulmonary arteries: preservation of the endothelial nitric oxide-dependent beta2 component in pulmonary hypertension.
abstract: OBJECTIVE
  beta-adrenoceptor (beta-AR)-mediated relaxation was characterized in pulmonary arteries from normoxic and hypoxic (as model of pulmonary hypertension) mice. The endothelial NO synthase (eNOS) pathway was especially investigated because of its potential vasculoprotective effects.
  
  
  METHODS
  Pulmonary arteries from control or hypoxic (0.5 atm for 21 days) wild-type or eNOS-/- mice were used for pharmacological characterization of beta-AR-mediated relaxation in myograph, and for immunohistochemistry using anti-beta-AR antibodies.
  
  
  RESULTS
  In pulmonary arteries from normoxic mice, isoproterenol (beta-AR agonist) and procaterol (selective beta2-AR agonist) elicited relaxation, while cyanopindolol and CL316243 (beta3-AR agonists) were ineffective. The effect of isoproterenol was antagonized by CGP20712A and ICI118551 (beta1- or beta2-AR antagonists, respectively) and also partially inhibited by N omega-nitro-L-arginine methylester (L-NAME, a NOS inhibitor), endothelium denudation, or eNOS gene deletion. Relaxation to procaterol was abolished by L-NAME or endothelium removal. In eNOS-/- mice, procaterol-induced relaxation was decreased but was insensitive to L-NAME, this residual effect involving other endothelium-dependent relaxant factors as compensatory mechanisms. Immunostaining for beta2-AR was observed in the endothelial layer, but not the medial layer of pulmonary arteries. Pulmonary arteries from hypoxic mice exhibited decreased endothelial NO-dependent relaxation to acetylcholine. However, in these arteries, relaxation to procaterol was either unaffected (extralobar segments) or even increased (intralobar segments) and was still abolished by L-NAME or endothelium removal.
  
  
  CONCLUSIONS
  beta1- and beta2-AR, but not beta3-AR, mediate relaxation of mice pulmonary arteries. The beta2-AR component is dependent on eNOS activity and is preserved following chronic hypoxia. These data highlight the role of the beta2-AR as a pharmacological target to induce/restore endothelial NO-dependent protective effects in pulmonary circulation.
authors.affiliation: Université Bordeaux 2, Laboratoire de Pharmacologie de l'UFR Pharmacie, Bordeaux F-33076, France. veronique.leblais@phcodyn.u-bordeaux2.fr
authors.forename: Véronique
authors.initials: V
authors.lastname: Leblais
authors.forename: Estelle
authors.initials: E
authors.lastname: Delannoy
authors.forename: Fleur
authors.initials: F
authors.lastname: Fresquet
authors.forename: Hugues
authors.initials: H
authors.lastname: Bégueret
authors.forename: Nadège
authors.initials: N
authors.lastname: Bellance
authors.forename: Sébastien
authors.initials: S
authors.lastname: Banquet
authors.forename: Cécile
authors.initials: C
authors.lastname: Allières
authors.forename: Lionel
authors.initials: L
authors.lastname: Leroux
authors.forename: Claude
authors.initials: C
authors.lastname: Desgranges
authors.forename: Alain
authors.initials: A
authors.lastname: Gadeau
authors.forename: Bernard
authors.initials: B
authors.lastname: Muller
mesh_terms: D000818:Animals; D002908:Chronic Disease; D004730:Endothelium, Vascular / Q000502:physiology*; D006976:Hypertension, Pulmonary / Q000503:physiopathology* / Q000517:prevention & control; D000860:Hypoxia / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D011651:Pulmonary Artery / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000145:classification; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D014664:Vasodilation
chemical_list: D017382:Reactive Oxygen Species; D011943:Receptors, Adrenergic, beta; D018343:Receptors, Adrenergic, beta-2; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019331:NG-Nitroarginine Methyl Ester