Beta-adrenoceptor regulation and functional responses in the guinea-pig following chronic administration of the long-acting beta 2-adrenoceptor agonist formoterol.

Formoterol is a long acting beta 2-adrenoceptor agonist designed for the alleviation of the symptoms of asthma. This study examined the effects of 14 day administration of formoterol (200 micrograms/kg/day i.p.) on beta 1- and beta 2-adrenoceptors in guinea-pig cardiac and lung tissue. Quantitative autoradiography was used to measure changes in receptor density and organ bath studies determined alterations in functional response. Formoterol treatment produced marked reductions of between 43% and 77% in beta 2-adrenoceptor density in all regions of the heart (atrioventricular node, bundle of His, right and left bundle branches, interventricular and interatrial septa, right and left atria, ventricles and apex) and lung (bronchial and vascular smooth muscle and parenchyma) (P < 0.01, n = 6). beta 1-Adrenoceptor density remained unchanged in all cardiac and lung regions. In functional studies (-)-isoprenaline was 4 fold less potent at causing relaxation of carbachol (1 microM) precontracted tracheal smooth muscle (pD2: control 8.49 +/- 0.03, formoterol 7.91 +/- 0.10, P < 0.001, n = 4), but formoterol treatment did not change the ability of (-)-isoprenaline to elicit a maximum response. The pKB values for ICI 118,551, 7.33 +/- 0.08 in the control and 7.20 +/- 0.01 in formoterol treated animals, were between those expected for beta 1- and beta 2-adrenoceptors suggesting involvement of both subtypes in the response. In spontaneously beating right atria and electrically paced left atria, tissues in which responses are largely mediated by beta 1-adrenoceptors, there was no significant change in responses to (-)-isoprenaline (right atria pD2: control 8.45 +/- 0.02; formoterol 8.42 +/- 0.11; P = 0.77, n = 4) (left atria pD2: control 8.25 +/- 0.03; formoterol 8.47 +/- 0.08; P = 0.09, n = 4). In the presence of CGP 20712A (100 nM) the pKB values did not change with formoterol treatment (left atria: control 9.59 +/- 0.12, formoterol 9.66 +/- 0.12; P = 0.70, n = 4) (right atria: control 8.93 +/- 0.11, formoterol 9.11 +/- 0.07; P = 0.25, n = 4). The doses and route of administration of formoterol used in this study differs from those used clinically. However, this study demonstrates that chronic formoterol administration produces selective down-regulation of beta 2-adrenoceptors in the lung and heart. The changes in the lung are accompanied by a shift to the right in the concentration-response curve to beta-agonist stimulation with no change in the maximum response.