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.
Hayes
M J
MJ
Medical Research Council, Clinical Sciences Center, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom.
Qing
F
F
Rhodes
C G
CG
Rahman
S U
SU
Ind
P W
PW
Sriskandan
S
S
Jones
T
T
Hughes
J M
JM
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