Relationship between nonspecific bronchial responsiveness to methacholine and peripheral mononuclear leukocyte beta-adrenergic receptor function in young drug-naive subjects.
Asthma is associated with dysfunction of the beta-adrenergic receptor adenylyl cyclase signal transduction pathway. It has been argued that this results from receptor down-regulation by beta-agonist therapy. This study examined the relationship between nonspecific bronchial responsiveness (NSBR) to methacholine (Newcastle dosimeter method) and beta-adrenergic receptor density (Bmax) and affinity (%KH) in membranes from peripheral blood mononuclear leukocytes (MNL) in 12 male (27.3 +/- 1.7 yr old) and 14 female (31.4 +/- 1.7 yr old) drug-naive subjects with and without symptoms of mild intermittent wheezing. None had ever smoked or received any antiasthma medication. "Hyperresponsive" subjects were defined as those (n = 11) whose simplified slope of FEF50 (calculated as the percent fall in FEF50 divided by the dose of methacholine) was more than one SD above the mean for asymptomatic subjects. The log of the slope was reproducible (repeatability coefficient = 0.43) on two nonconsecutive days. Multiple regression analysis (overall R2 = 0.57) revealed negative relationships between the log of the slope and both Bmax (p = 0.016) and %KH (p = 0.011). Analysis of variance confirmed a lower mean (+/- SEM) value of %KH in "hyperresponsives" (45.7 +/- 5.5%) than in "normoresponsives" (60.4 +/- 4.1%, p = 0.04) with a similar trend for Bmax (hyperresponsives = 33.5 +/- 4.1 fmol/mg, normoresponsives = 45.9 +/- 7.1 fmol/mg, p = 0.18). These relationships between bronchial responsiveness, Bmax, and %KH cannot be explained by drug therapy, and they provide further evidence that there is an intrinsic impairment in the function of beta-adrenergic receptors on peripheral MNLs from subjects with high levels of nonspecific bronchial responsiveness.
Connolly
M J
MJ
Clinical Pharmacology and Gerontology Research Unit, Veterans Affairs Medical Center, Boise, Idaho 83702.
Crowley
J J
JJ
Nielson
C P
CP
Charan
N B
NB
Vestal
R E
RE
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D001980:Bronchi / Q000187:drug effects* / Q000502:physiology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000453:epidemiology / Q000503:physiopathology; D001985:Bronchial Provocation Tests / Q000379:methods / Q000706:statistics & numerical data; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008450:Maximal Midexpiratory Flow Rate / Q000187:drug effects / Q000502:physiology; D016210:Methacholine Chloride / Q000494:pharmacology*; D008875:Middle Aged; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000502:physiology; D012044:Regression Analysis; D012135:Respiratory Sounds / Q000187:drug effects / Q000502:physiology
D011943:Receptors, Adrenergic, beta; D016210:Methacholine Chloride