title: Changes in beta 2-adrenoceptor and other signaling proteins produced by chronic administration of 'beta-blockers' in a murine asthma model.
abstract: BACKGROUND
  We have previously reported that chronic treatment with certain 'beta-blockers' reduces airway hyperresponsiveness (AHR) to methacholine in a murine model of asthma.
  
  
  METHODS
  Airway resistance was measured using the forced oscillation technique in ovalbulmin-sensitized and ovalbulmin-challenged mice treated with several beta-adrenoceptor (beta-AR) ligands. We used the selective beta 2-AR ligand ICI 118,551 and the preferential beta 1-AR ligand metoprolol to investigate the receptor subtype mediating the beneficial effect. Expression of beta-ARs was evaluated using immunofluorescence. We evaluated several signaling proteins by western blot using lung homogenates, and measured the relaxation of the isolated trachea produced by EP2 and IP receptor agonists.
  
  
  RESULTS
  Four findings were associated with the decreased AHR after chronic beta-blocker treatment: (1) the highly selective beta 2-AR antagonist/inverse agonist, ICI 118,551 produced the bronchoprotective effect; (2) beta 2-AR up-regulation resulted from chronic 'beta-blocker' treatment; (3) reduced expression of certain proteins involved in regulating bronchial tone, namely, Gi, phosphodiesterase 4D and phospholipase C-beta 1; and (4) an enhanced bronchodilatory response to prostanoid agonists for the IP and EP2 receptors.
  
  
  CONCLUSIONS
  These data suggest that in the murine model of asthma, several compensatory changes associated with either increased bronchodilator signaling or decreased bronchoconstrictive signaling, result from the chronic administration of certain 'beta-blockers'.
authors: Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA.
authors: Rui
authors: R
authors: Lin
authors: Hui
authors: H
authors: Peng
authors: Long P
authors: LP
authors: Nguyen
authors: Noor B
authors: NB
authors: Dudekula
authors: Felix
authors: F
authors: Shardonofsky
authors: Brian J
authors: BJ
authors: Knoll
authors: Sergio
authors: S
authors: Parra
authors: Richard A
authors: RA
authors: Bond
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D001985:Bronchial Provocation Tests; D004334:Drug Administration Schedule; D005455:Fluorescent Antibody Technique; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D016210:Methacholine Chloride; D008790:Metoprolol / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009248:Nadolol / Q000494:pharmacology; D010047:Ovalbumin / Q000276:immunology; D011412:Propanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*
chemical_list: D000319:Adrenergic beta-Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; D016210:Methacholine Chloride; D009248:Nadolol; C026777:ICI 118551; D010047:Ovalbumin; D008790:Metoprolol
references: Lancet. 1982 Aug 21;2(8295):444
references: 6124836
references: Am Rev Respir Dis. 1980 Sep;122(3):365-71
references: 7416612
references: Am Rev Respir Dis. 1986 Feb;133(2):264-8
references: 3946922
references: Am J Ophthalmol. 1986 Nov 15;102(5):606-11
references: 3777080
references: Thorax. 1988 Apr;43(4):300-5
references: 2970125
references: Br Med J. 1968 Feb 10;1(5588):339-43
references: 5317526
references: Am Rev Respir Dis. 1989 Nov;140(5):1410-5
references: 2554767
references: Br J Pharmacol. 1990 Jan;99(1):136-44
references: 1970491
references: J Toxicol Sci. 1990 Feb;15(1):1-13
references: 1970836
references: Trends Pharmacol Sci. 1990 May;11(5):190-4
references: 2188401
references: Circ Res. 1990 Jun;66(6):1610-23
references: 1971535
references: Allergol Immunopathol (Madr). 1990 May-Jun;18(3):115-9
references: 2174641
references: J Biotechnol. 1991 Jan;17(1):67-80
references: 1367495
references: N Engl J Med. 1992 Feb 20;326(8):501-6
references: 1346340
references: J Pharmacol Exp Ther. 1992 Dec;263(3):1195-205
references: 1335058
references: Life Sci. 1993;52(26):2101-9
references: 8389953
references: Chest. 1993 Aug;104(2):508-14
references: 8393400
references: Am J Respir Crit Care Med. 1994 Mar;149(3 Pt 1):604-10
references: 8118625
references: Naunyn Schmiedebergs Arch Pharmacol. 1994 Apr;349(4):331-7
references: 7914677
references: Mol Pharmacol. 1995 Feb;47(2):322-9
references: 7870040
references: J Am Coll Cardiol. 1995 Apr;25(5):1154-61
references: 7897129
references: Am J Physiol. 1995 Nov;269(5 Pt 1):L645-52
references: 7491984
references: N Engl J Med. 1996 May 23;334(21):1349-55
references: 8614419
references: Naunyn Schmiedebergs Arch Pharmacol. 1996 May;353(6):661-70
references: 8738299
references: N Engl J Med. 1996 Sep 19;335(12):841-7
references: 8778601
references: Circulation. 1998 Sep 22;98(12):1184-91
references: 9743509
references: Am J Physiol. 1998 Oct;275(4 Pt 1):L694-700
references: 9755101
references: Pulm Pharmacol Ther. 1998 Feb;11(1):47-56
references: 9802963
references: Circ Res. 1999 Jan 8-22;84(1):43-52
references: 9915773
references: Mol Pharmacol. 1999 May;55(5):863-72
references: 10220565
references: Thorax. 1998 Sep;53(9):744-52
references: 10319056
references: Br J Pharmacol. 2005 Feb;144(3):317-22
references: 15655528
references: Biochemistry. 2005 Oct 25;44(42):13771-82
references: 16229467
references: Respir Res. 2005;6:107
references: 16168062
references: Br J Pharmacol. 2006 Jan;147 Suppl 1:S297-303
references: 16402117
references: Chest. 2006 Jan;129(1):15-26
references: 16424409
references: Eur J Pharmacol. 2006 Mar 8;533(1-3):15-27
references: 16469310
references: Circ Res. 2000 Oct 13;87(8):705-9
references: 11029407
references: Trends Pharmacol Sci. 2000 Aug;21(8):291-2
references: 10918631
references: Lancet. 1990 Jul 7;336(8706):1-6
references: 1694945
references: Biochem Pharmacol. 2001 Apr 1;61(7):921-4
references: 11274979
references: Sci STKE. 2001 Oct 16;2001(104):re15
references: 11604549
references: Eur J Pharmacol. 2002 Jun 7;445(1-2):1-12
references: 12065188
references: J Biol Chem. 2002 Sep 27;277(39):35980-9
references: 12121997
references: J Appl Physiol (1985). 2003 Jan;94(1):245-52
references: 12486022
references: J Biol Chem. 2003 Feb 21;278(8):5493-6
references: 12493749
references: J Clin Invest. 2003 Aug;112(4):619-26
references: 12925702
references: Am J Forensic Med Pathol. 2003 Sep;24(3):271-2
references: 12960663
references: Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):4948-53
references: 15069206
references: J Appl Physiol (1985). 2004 Jun;96(6):2019-27
references: 14660507
references: Respir Physiol Neurobiol. 2004 Oct 12;143(1):77-86
references: 15477174
references: Ann N Y Acad Sci. 1979;332:295-8
references: 231405
references: Triangle. 1979;18(4):109-15
references: 232320
references: Eur J Pharmacol. 1985 Oct 22;116(3):279-85
references: 2866967