Abstract
The relaxant responses of the beta(2)-adrenoceptor agonist salbutamol and NKH477, an activator of adenylate cyclase, were compared and the possible potentiating effect of NKH477 on salbutamol-induced bronchodilatation was measured together with the effectiveness of NKH477 in reversing tachyphylaxis development to salbutamol. The in vitro bronchodilator effect of salbutamol and NKH477 (10(-9) - 10(-5) M) was measured on isolated guinea pig tracheal ring segments precontracted with carbachol (10(-6) M). Both salbutamol and NKH477 produced a concentration-dependent relaxation. EC50 values were determined from cumulative concentration-response curves. Salbutamol was more potent than NKH477 in relaxing the tracheal preparations (7.1 +/- 0.1 compared to 6.1 +/- 0.2, respectively). NKH477 produced a significant increase in the salbutamol-induced bronchodilator effect. The potency values recorded for salbutamol were 7.1 +/- 0.1, 7.4 +/- 0.2, 7.6 +/- 0.1, and 8.6 +/- 0.4 in the absence and presence of NKH477 (3 x 10(-8) M, 10(-7) M, and 3 x 10(-7) M, respectively). Reproducible relaxant responses could be elicited to salbutamol and NKH477 after 24 h incubation in Krebs' solution. Tachyphylaxis to the relaxant effects of salbutamol was experimentally induced by 24-h incubation of the preparations in Krebs' solution containing salbutamol (10(-6), 3 X 10(-6) or 10(-5) M). The potency of salbutamol was reduced to 6.9 +/- 0.2, 6.8 +/- 0.2, and 6.0 +/- 0.2 after 24 h incubation with salbutamol 10(-6) M, 3 X 10(-6) M or 10(-5) M, respectively. NKH477 (3 x 10(-7) M) produced a complete reversal of tachyphylaxis to salbutamol-induced relaxation in salbutamol pretreated tissues. The potency of salbutamol was increased to 7.4 +/- 0.2, 7.1 +/- 0.1, and 7.3 +/- 0.1 after the addition of NKH477 (3 x 10(-7) M) to the preparations preincubated (24 h) with salbutamol 10(-6), 3 X 10(-6), or 10(-5) M, respectively. NKH477 shares with salbutamol the ability to relax airway smooth muscle and produces an apparent increase of the bronchodilator effects of salbutamol and reverses tachyphylaxis. Drug Dev. Res. 48:154-159, 1999. (C) 1999 Wiley-Liss, Inc.
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