Different effects of beta-adrenoceptor desensitization on inhibitory actions in guinea-pig trachealis.

1. To determine the inhibitory effects of agents that pass through and bypass beta-adrenoceptors under conditions of tolerance to beta-adrenoceptor agonists, we examined the inhibition by the beta-adrenoceptor agonists forskolin and theophylline against contraction induced by methacholine (MCh) after exposure to higher concentrations of a beta-adrenoceptor agonist for a long time in guinea-pig tracheal smooth muscle, using isometric tension records. 2. After exposure to procaterol (0.0003-3 micromol/L) for 45 min, the inhibitory effect of 0.03 micromol/L procaterol on 1 micromol/L MCh-induced contraction was attenuated in a concentration-dependent manner, whereas after exposure to isoprenaline (0.0003-3 micromol/L) for an equivalent time, the inhibitory effect of isoprenaline was markedly attenuated at each concentration. However, after exposure to 3 micromol/L procaterol for 45 min, the inhibitory actions of forskolin and theophylline were, conversely, augmented. 3. These phenomena were observed under conditions whereby the response to MCh returned to control levels 6 h after removal of 3 micromol/L procaterol. The percentage inhibition produced by 0.1 micromol/L forskolin against 1 micromol/L MCh after exposure to normal bathing solution or 3 micromol/L procaterol for 45 min was 9.8 +/- 5.5 and 82.8 +/- 6.5%, respectively (P < 0.001). These values for 100 micromol/L (18 microg/mL) theophylline on MCh resposnes were 9.9 +/- 8.5 and 88.0 +/- 4.4% (n = 6 for both), respectively (P < 0.001). 4. The inhibitory action of agents that bypass beta-adrenoceptors was markedly augmented under conditions of beta-adrenoceptor desensitization in airway smooth muscle. 5. In conclusion, procaterol is less potent in causing desensitization of beta-adrenoceptors than isoprenaline. The activity of adenylyl cyclase may be enhanced after exposure to a high concentration of beta-adrenoceptor agonists.