Changes in beta 2-adrenoceptor and other signaling proteins produced by chronic administration of 'beta-blockers' in a murine asthma model.
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'.
Lin
Rui
R
Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA.
Peng
Hui
H
Nguyen
Long P
LP
Dudekula
Noor B
NB
Shardonofsky
Felix
F
Knoll
Brian J
BJ
Parra
Sergio
S
Bond
Richard A
RA
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*
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
Lancet. 1982 Aug 21;2(8295):444
6124836
Am Rev Respir Dis. 1980 Sep;122(3):365-71
7416612
Am Rev Respir Dis. 1986 Feb;133(2):264-8
3946922
Am J Ophthalmol. 1986 Nov 15;102(5):606-11
3777080
Thorax. 1988 Apr;43(4):300-5
2970125
Br Med J. 1968 Feb 10;1(5588):339-43
5317526
Am Rev Respir Dis. 1989 Nov;140(5):1410-5
2554767
Br J Pharmacol. 1990 Jan;99(1):136-44
1970491
J Toxicol Sci. 1990 Feb;15(1):1-13
1970836
Trends Pharmacol Sci. 1990 May;11(5):190-4
2188401
Circ Res. 1990 Jun;66(6):1610-23
1971535
Allergol Immunopathol (Madr). 1990 May-Jun;18(3):115-9
2174641
J Biotechnol. 1991 Jan;17(1):67-80
1367495
N Engl J Med. 1992 Feb 20;326(8):501-6
1346340
J Pharmacol Exp Ther. 1992 Dec;263(3):1195-205
1335058
Life Sci. 1993;52(26):2101-9
8389953
Chest. 1993 Aug;104(2):508-14
8393400
Am J Respir Crit Care Med. 1994 Mar;149(3 Pt 1):604-10
8118625
Naunyn Schmiedebergs Arch Pharmacol. 1994 Apr;349(4):331-7
7914677
Mol Pharmacol. 1995 Feb;47(2):322-9
7870040
J Am Coll Cardiol. 1995 Apr;25(5):1154-61
7897129
Am J Physiol. 1995 Nov;269(5 Pt 1):L645-52
7491984
N Engl J Med. 1996 May 23;334(21):1349-55
8614419
Naunyn Schmiedebergs Arch Pharmacol. 1996 May;353(6):661-70
8738299
N Engl J Med. 1996 Sep 19;335(12):841-7
8778601
Circulation. 1998 Sep 22;98(12):1184-91
9743509
Am J Physiol. 1998 Oct;275(4 Pt 1):L694-700
9755101
Pulm Pharmacol Ther. 1998 Feb;11(1):47-56
9802963
Circ Res. 1999 Jan 8-22;84(1):43-52
9915773
Mol Pharmacol. 1999 May;55(5):863-72
10220565
Thorax. 1998 Sep;53(9):744-52
10319056
Br J Pharmacol. 2005 Feb;144(3):317-22
15655528
Biochemistry. 2005 Oct 25;44(42):13771-82
16229467
Respir Res. 2005;6:107
16168062
Br J Pharmacol. 2006 Jan;147 Suppl 1:S297-303
16402117
Chest. 2006 Jan;129(1):15-26
16424409
Eur J Pharmacol. 2006 Mar 8;533(1-3):15-27
16469310
Circ Res. 2000 Oct 13;87(8):705-9
11029407
Trends Pharmacol Sci. 2000 Aug;21(8):291-2
10918631
Lancet. 1990 Jul 7;336(8706):1-6
1694945
Biochem Pharmacol. 2001 Apr 1;61(7):921-4
11274979
Sci STKE. 2001 Oct 16;2001(104):re15
11604549
Eur J Pharmacol. 2002 Jun 7;445(1-2):1-12
12065188
J Biol Chem. 2002 Sep 27;277(39):35980-9
12121997
J Appl Physiol (1985). 2003 Jan;94(1):245-52
12486022
J Biol Chem. 2003 Feb 21;278(8):5493-6
12493749
J Clin Invest. 2003 Aug;112(4):619-26
12925702
Am J Forensic Med Pathol. 2003 Sep;24(3):271-2
12960663
Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):4948-53
15069206
J Appl Physiol (1985). 2004 Jun;96(6):2019-27
14660507
Respir Physiol Neurobiol. 2004 Oct 12;143(1):77-86
15477174
Ann N Y Acad Sci. 1979;332:295-8
231405
Triangle. 1979;18(4):109-15
232320
Eur J Pharmacol. 1985 Oct 22;116(3):279-85
2866967