A pharmacological study of bronchodilator properties of NKH477, forskolin,and beta-agonists on guinea pig and ovine isolated bronchioles

In this study we assessed the relaxant responses of two direct adenylate cy clase activators, NKH477 and forskolin, in comparison with two beta -adreno ceptor agonists, salbutamol and isoprenaline. The possible potentiation eff ect of NKH477 and forskolin on beta -agonist-induced bronchodilatation was examined. The effectiveness of NKH477 and forskolin in reversing tachyphyla xis development to salbutamol or isoprenaline was also investigated. We tes ted the in vitro bronchodilator effect of salbutamol, NKH477, and forskolin (10(-9)-10(-4) M) On isolated guinea pig bronchiolar ring segments precont racted with carbachol (3 muM). Salbutamol, NKH477, and forskolin produced a concentration-dependent relaxation. Potency values (pD(2)) were determined from cumulative concentration-response curves. The rank order for their po tencies was salbutamol > NKH477 > forskolin (7.3 +/- 0.3, 6.4 +/- 0.3, and 5.4 +/- 0.1, respectively). The bronchodilator effects of salbutamol, isopr enaline, NKH477, and forskolin (10(-9)-10(-4) M) were examined on isolated ovine bronchioles precontracted with carbachol (0.3 muM). Isoprenaline, NKH 477, and forskolin produced a concentration-dependent relaxation with pot v alues of 6.1 +/- 0.2, 5.4 +/- 0.2, and 5.3 +/- 0.2, respectively. Tachyphyl axis to the relaxant effects of salbutamol on guinea pig isolated bronchiol es was experimentally induced and the potency of salbutamol was reduced to 5.9 +/- 0.2 after 24 h incubation with salbutamol (10(-5) M). NKH477 and fo rskolin (10(-6) M) produced a partial reversal of tachyphylaxis to salbutam ol-induced relaxation using salbutamol pretreated tissues. The potency of s albutamol was increased to 6.6 +/- 0.2 and 5.9 +/- 0.2 after incubation wit h NKH477 or forskolin (10(-6) M), respectively Tachyphylaxis to the relaxan t effects of isoprenaline resulted in a reduced potency of 5.7 +/- 0.2. For skolin (10-6 M) Produced a partial reversal of tachyphylaxis, while NKH477 (10(-6) M) produced a complete reversal of tachyphylaxis to isoprenaline-in duced relaxation with an pot value of 6.3 +/- 0.1. In conclusion, the guine a pig and sheep isolated bronchioles serve as good models to study the rela xant effects of the bronchodilator agents salbutamol, isoprenaline, NKH477, and forskolin. The beta -agonists examined had higher potencies than NKH47 7 or forskolin. However, the two adenylate cyclase activators, with greater effectiveness of NKH477, when used in combination with the beta -agonists, could produce an increase in the potency of the beta -agonists. Furthermor e, the effectiveness of NKH477 and forskolin in reversing tachyphylaxis to the bronchodilator effects of the beta -agonists, particularly salbutamol, may provide an advantage in long-term use of beta -agonists in bronchial as thma therapy. Drug Dev. Res. 51:169-176, 2000. (C) 2001 Wiley-Liss, Inc.