title: β-Blockers have differential effects on the murine asthma phenotype.
abstract: OBJECTIVE
  Our previous studies have shown the β2 -adrenoceptor and its endogenous ligand, adrenaline, are required for development of the asthma phenotype in murine asthma models. Chronic administration of some, but not other, β-blockers attenuated the asthma phenotype and led us to hypothesize that biased signalling was the basis of their differential effects, experimentally and clinically.
  
  
  METHODS
  We used mice with no detectable systemic adrenaline (PNMT(-/-) ) and wild-type (WT) mice to study the effects of four β-blockers, alprenolol, carvedilol, propranolol and nadolol, in an ovalbumin sensitization and challenge (Ova S/C) murine model of asthma. The parameters measured were inflammatory cell infiltration, mucous metaplasia and airway hyperresponsiveness. To interpret the pharmacological action of these ligands quantitatively, we conducted computer simulations of three-state models of receptor activation.
  
  
  RESULTS
  Ova S/C PNMT(-/-) mice do not develop an asthma phenotype. Here, we showed that administration of alprenolol, carvedilol or propranolol in the absence of interference from adrenaline using Ova S/C PNMT(-/-) mice resulted in the development of an asthma phenotype, whereas nadolol had no effect. Ova S/C WT mice did develop an asthma phenotype, and administration of alprenolol, propranolol and carvedilol had no effect on the asthma phenotype. However, nadolol prevented development of the asthma phenotype in Ova S/C WT mice. Computer simulations of these four ligands were consistent with the isolated three-state receptor model.
  
  
  CONCLUSIONS
  β-Blockers have different effects on the murine asthma phenotype that correlate with reported differences in activation or inhibition of downstream β2 -adrenoceptor signalling pathways.
authors.affiliation: Department of Integrative and Biology Pharmacology, University of Texas Health Science Center, Houston, TX, USA.
authors.forename: V J
authors.initials: VJ
authors.lastname: Thanawala
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Valdez
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Joshi
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin, Milwaukee Institute for Drug Discovery, Milwaukee, WI.
authors.forename: G S
authors.initials: GS
authors.lastname: Forkuo
authors.affiliation: Vapogenix, Inc., Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Parra
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Knoll
authors.affiliation: Department of Biochemistry, Université de Montréal, Montréal, QC, Canada.|Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Bouvier
authors.affiliation: Consultant in Pharmacology, Cheshire, UK.
authors.forename: P
authors.initials: P
authors.lastname: Leff
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Bond
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000485:Allergens; D000526:Alprenolol / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002227:Carbazoles / Q000494:pharmacology; D000077261:Carvedilol; D002452:Cell Count; D004837:Epinephrine / Q000172:deficiency; D005260:Female; D008297:Male; D018345:Mice, Knockout; D008954:Models, Biological; D009077:Mucins / Q000378:metabolism; D009248:Nadolol / Q000494:pharmacology; D010047:Ovalbumin; D010641:Phenotype; D011412:Propanolamines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology
chemical_list: D000319:Adrenergic beta-Antagonists; D000485:Allergens; D002227:Carbazoles; D009077:Mucins; D011412:Propanolamines; D000077261:Carvedilol; D009248:Nadolol; D000526:Alprenolol; D010047:Ovalbumin; D011433:Propranolol; D004837:Epinephrine