Abstract
The objective of this study was to assess the relaxant responses of salbutamol, a beta2 agonist, and forskolin, an activator of adenylate cyclase, and the possible role of forskolin in reversing tachyphylaxis to salbutamol. The in-vitro bronchodilator effects of salbutamol and forskolin (10(-9)-10(-5) M) were tested on isolated guinea-pig tracheal rings precontracted with carbachol (10(-7) M). Both salbutamol and forskolin elicited concentration-dependent relaxation. Potency (EC50; the dose resulting in 50% relaxation) was determined from cumulative concentration-response curves. Salbutamol was more potent than forskolin in relaxing the tracheal preparations (-log molar EC50 7.68+/-0.14 and 6.3+/-0.17, respectively). Reproducible relaxant responses to salbutamol could be elicited after 24 h incubation in Krebs solution. Tachyphylaxis to the relaxant effects of salbutamol was experimentally induced by incubation (24h) of the preparations in Krebs solution containing salbutamol (10(-6) 3x10(-6) or 10(-5) M). This pretreatment of the tissues resulted in a significant reduction in the potency of salbutamol. The potency of salbutamol was reduced to 6.85+/-0.2, 6.8+/-0.1 and 5.9+/-0.27 after 24h incubation with salbutamol 10(-6), 3x10(-6) or 10(-5) M, respectively. The potency of salbutamol was increased from 7.35+/-0.2 to 7.76+/-0.28 by addition of forskolin (3x10(-7) M) under control conditions. Moreover, forskolin (3x10(-7) M) reversed the development of tachyphylaxis to salbutamol-induced relaxation in tissues pretreated with salbutamol. The potency of salbutamol was increased to 7.29+/-0.41, 7.37+/-0.17 and 7.23+/-0.35 after the addition of forskolin (3x10(-7) M) to preparations pre-incubated (24h) with salbutamol 10(-6), 3x10(-6) or 10(-5) M respectively. These results show that in guinea-pig tracheal ring preparations, forskolin shares with salbutamol the ability to relax airway smooth muscle and produces an apparent reversal of tachyphylaxis to the bronchodilator effects of salbutamol, particularly in the low concentration range. This effect could provide an alternative therapy for long term use, particularly with high doses of beta2 agonists in bronchial asthma.
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