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 eff ects of 14 day administration of formoterol (200 mu g/kg/day i.p.) on beta(1)- and beta(2)-adrenoceptors in guinea-pig cardiac and lung tiss ue. Quantitative autoradiography was used to measure changes in recept or 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 hear t (atrioventricular node, bundle of His, right and left bundle branche s, interventricular and interatrial septa, right and left atria, ventr icles and apex) and lung (bronchial and vascular smooth muscle and par enchyma) (P < 0.01, n = 6). beta(1)-Adrenoceptor density remained unch anged in all cardiac and lung regions. In functional studies (-)-isopr enaline was 4 fold less potent at causing relaxation of carbachol (1 m u M) precontracted tracheal smooth muscle (pD(2): control 8.49 +/- 0.0 3, formoterol 7.91 +/- 0.10, P < 0.001, n = 4), but formoterol treatme nt did not change the ability of (-)-isoprenaline to elicit a maximum response. The pK(B) values for ICI 118,551, 7.33 +/- 0.08 in the contr ol and 7.20 +/- 0.01 in formoterol treated animals, were between those expected for beta(1)- and beta(2)-adrenoceptors suggesting involvemen t of both subtypes in the response. In spontaneously beating right atr ia and electrically paced left atria, tissues in which responses are l argely mediated by beta(1)-adrenoceptors, there was no significant cha nge in responses to (-)isoprenaline (right atria pD(2): control 8.45 /- 0.02; formoterol 8.42 +/- 0.11; P = 0.77, n = 4) (left atria pot: c ontrol 8.25 +/- 0.03; formoterol 8.47 +/- 0.08; P = 0.09, n = 4). In t he presence of CGP 20712A (100 nM) the pK(B) values did not change wit h 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, f ormoterol 9.11 +/- 0.07; P = 0.25, n = 4). The doses and route of admi nistration of formoterol used in this study differs from those used cl inically. However, this study demonstrates that chronic formoterol adm inistration produces selective downregulation of beta(2)-adrenoceptors in the lung and heart. The changes in the lung are accompanied by a s hift to the right in the concentration-response curve to beta-agonist stimulation with no change in the maximum response.