Salmeterol, formoterol, and salbutamol in the isolated guinea pig trachea: Differences in maximum relaxant effect and potency but not in functional antagonism

Abstract

Background - Formoterol and salmeterol are new long acting β2 adrenoceptor agonists. The maximum relaxant effect, potency and functional antagonism against carbachol induced contraction for salmeterol, formoterol and salbutamol have been compared in the guinea pig isolated trachea. In addition, the possibility of inducing a non-β adrenoceptor mediated relaxation by salmeterol was studied. Methods - Concentration response experiments were conducted with isolated tracheal preparations (n = 4-6 in all experiments), precontracted by carbachol to cause either 40% (60 nmol/l), 80% (0.3 μmol/l) or 100% (3 μmol/l, supramaximal) of the maximum contraction. Each β agonist was added cumulatively at each level of precontraction. Additional cumulative concentration response experiments were conducted for salmeterol alone at the highest level of precontraction, with and without β blockade by sotalol (1 mmol/l). With the drug concentrations which produced the maximum response and the highest level of precontraction, the relaxation of formoterol (10 nmol/l) and salmeterol (1 μmol/l) was also compared non-cumulatively. Finally, with the corresponding drug concentrations and precontraction, the relaxant effect was compared for formoterol (10 nmol/l) in salmeterol relaxed airways with that of salmeterol (1 μmol/l) in formoterol relaxed airways. Results - The increase in carbachol concentration from 60 nmol/l to 3 μmol/l induced a rightward shift in the mean (SE) concentration (log steps) causing 50% maximum relaxation for salmeterol (0.73 (0.17)), formoterol (0.85 (0.18)), and salbutamol (1.13 (0.11)). Significant differences in the maximum relaxant effect were shown at the highest level of precontraction only, with a remaining active tension of percentage precontraction of 27% (4%) for 1 μmol/l salbutamol and 35% (3%)for 10 nmol/l formoterol compared with 50% (2%) for 1 μmol/l salmeterol. The rank order of potency was: formoterol > salbutamol ~ salmeterol at all levels of precontraction (-log EC50: 9.32 (0.05) for formoterol, 7.82 (0.08) for salbutamol, and 7.50 (0.13) for salmeterol at 80% maximum precontraction). Beta blockade by sotalol (1 mmol/l) significantly inhibited the relaxation induced by salmeterol (1 μmol/l) (remaining active tension: 104% (1%) v 71% (11%) of precontraction) but not the relaxation induced by salmeterol (10 μmol/l) (remaining active tension: 75% (5%) v 71% (12%) of precontraction). In the non-cumulative experiments, formoterol displayed more relaxant effect than salmeterol (remaining active tension: 51% (6%) v 65% (6%) of precontraction). Finally, formoterol significantly relaxed salmeterol relaxed airways (relaxant effect: 22% (8%) of precontraction) whereas there was no significant response to salmeterol in formoterol relaxed airways (relaxant effect: 5% (12%) of precontraction). Conclusions - In the guinea pig isolated trachea, formoterol and salbutamol produce more relaxant effect than salmeterol, suggesting that salmeterol is a partial β2 agonist. Very high concentrations of salmeterol may induce non-β adrenoceptor mediated relaxation. Formoterol is more potent than both salbutamol and salmeterol. There is no pronounced difference in the magnitude of antagonism against carbachol induced contractions between salmeterol, formoterol, and salbutamol.