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

The relaxant responses of the beta(2)-adrenoceptor agonist salbutamol and N KH477, an activator of adenylate cyclase, were compared and the possible po tentiating effect of NKH477 on salbutamol-induced bronchodilatation was mea sured 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 trachea l ring segments precontracted with carbachol (10(-6) M). Both salbutamol an d NKH477 produced a concentration-dependent relaxation. EC50 values were de termined from cumulative concentration-response curves. Salbutamol was more potent than NKH477 in relaxing the tracheal preparations (7.1 +/- 0.1 comp ared to 6.1 +/- 0.2, respectively). NKH477 produced a significant increase in the salbutamol-induced bronchodilator effect. The potency values recorde d 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. Tachyphyla xis 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 salbuta mol 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 relaxa tion in salbutamol pretreated tissues. The potency of salbutamol was increa sed to 7.4 +/- 0.2, 7.1 +/- 0.1, and 7.3 +/- 0.1 after the addition of NKH4 77 (3 x 10(-7) M) to the preparations preincubated (24 h) with salbutamol 1 0(-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 increas e of the bronchodilator effects of salbutamol and reverses tachyphylaxis. D rug Dev. Res. 48:154-159, 1999. (C) 1999 Wiley-Liss, Inc.