In vivo quantification of human pulmonary beta-adrenoceptors: effect of beta-agonist therapy.
In human subjects, chronic beta2-agonist dosing reduces mononuclear leukocyte (MNL) beta-adrenoceptor numbers. The aim of this study was to investigate whether this downregulation also occurs in the lung. Seven healthy male subjects were treated for 2 wk with oral (up to 16 mg/d) and inhaled (up to 1.6 mg/d) albuterol (salbutamol in Europe). Pulmonary maximal beta-adrenoceptor binding capacity (Bmax) was determined in vivo using positron emission tomography (PET) and the beta-receptor antagonist ligand, 11C-labeled CGP-12177, before and after the 2-wk chronic dosing. MNL Bmax was also measured, using a radioligand binding assay and 3H-labeled CGP-12177. Bronchodilator responses to the beta2-agonist were determined after each PET scan by measuring the change in specific airway conductance (SGaw) after increasing doses of inhaled albuterol. Pulmonary and MNL Bmax fell by 22% +/- 14% (p < 0.05) and 42% +/- 19% (p < 0.05) respectively. The changes in pulmonary and MNL Bmax were correlated (r = 0.9, p < 0.05). There was also a reduction in the bronchodilator response to inhaled albuterol. In a further six subjects, pulmonary and MNL Bmax did not change during an acute infusion of albuterol (2 to 4 microg/kg/h). The reduction in pulmonary beta-adrenoceptor numbers after chronic albuterol dosing may be predictable from the changes observed in circulating MNL cells.
Medical Research Council, Clinical Sciences Center, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom.
M J
MJ
Hayes
F
F
Qing
C G
CG
Rhodes
S U
SU
Rahman
P W
PW
Ind
S
S
Sriskandan
T
T
Jones
J M
JM
Hughes
D000280:Administration, Inhalation; D000284:Administration, Oral; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000328:Adult; D000420:Albuterol / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D002395:Catecholamines / Q000097:blood; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008168:Lung / Q000187:drug effects*; D008297:Male; D009000:Monocytes / Q000187:drug effects; D011412:Propanolamines / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D015203:Reproducibility of Results; D014055:Tomography, Emission-Computed
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002395:Catecholamines; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D000420:Albuterol; C033394:CGP 12177