NKH477: A novel bronchodilator produces potentiation and tachyphylaxis reversal to salbutamol in isolated guinea pig trachea

Abstract

The relaxant responses of the β2-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 × 10–8 M, 10–7 M, and 3 × 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 × 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 × 10–6 M or 10–5 M, respectively. NKH477 (3 × 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 × 10–7 M) to the preparations preincubated (24 h) with salbutamol 10–6, 3 × 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. © 1999 Wiley-Liss, Inc.