Effect of long-term beta2-agonist dosing on human cardiac beta-adrenoceptor expression in vivo: comparison with changes in lung and mononuclear leukocyte beta-receptors.

BACKGROUND: Tachyphylaxis to the cardiac effects of beta-adrenoceptor stimulation after long-term beta2-agonist administration is well recognized, but the influence on global cardiac beta-adrenoceptor density has not been previously investigated in vivo. Positron emission tomography (PET) has made possible the noninvasive quantification of regional receptor density. This study assesses the effect of long-term beta2-agonist dosing on cardiac beta-adrenoceptors. METHODS AND
RESULTS: Beta-adrenoceptors in the hearts of 29 healthy male subjects aged 35 +/- 8 years were imaged and quantified in vivo by means of PET and compared with the receptor density in the same subjects' lung tissue. Mononuclear leukocyte (MNL) beta-receptor density was determined in vitro by means of a radioligand binding assay. Beta-receptor density was 8.41 +/- 2.03 pmol/gm tissue in heart, 10.81 +/- 1.91 pmol/gm tissue in lung, and 38.0 +/- 17.5 fmol/mg protein on MNLs. There was a weak relationship between cardiac and pulmonary beta-receptor densities (r = 0.45, p < 0.02) but not between cardiac and MNL receptor density. In seven subjects, the measurements were repeated after 2 weeks of albuterol treatment (4 mg orally twice daily and 200 microg inhaled four times daily in the first week, with doubling of the dose during the second week). After the albuterol treatment, beta-receptor density fell on average by 19% (p < 0.05) in the heart compared with 22% (p < 0.05) in the lung and 42% (p < 0.05) in MNLs. Correlations were found between the percentage changes in receptor density in heart and lung (r = 0.98, p < 0.001) and in heart and MNLs (r = 0.99, p < 0.002).
CONCLUSIONS: Two weeks of high-dose albuterol results in equivalent downregulation of beta-receptors in vivo, both in the lung and in the heart.