A pharmacological study of bronchodilator properties of NKH477, forskolin, and beta-agonists on guinea pig and ovine isolated bronchioles
2000 (English)In: Drug development research (Print), ISSN 0272-4391, Vol. 51, no 3, 169-176 p.Article in journal (Refereed) Published
In this study we assessed the relaxant responses of two direct adenylate cyclase activators, NKH477 and forskolin, in comparison with two beta -adrenoceptor agonists, salbutamol and isoprenaline. The possible potentiation effect of NKH477 and forskolin on beta -agonist-induced bronchodilatation was examined. The effectiveness of NKH477 and forskolin in reversing tachyphylaxis development to salbutamol or isoprenaline was also investigated. We tested the in vitro bronchodilator effect of salbutamol, NKH477, and forskolin (10(-9)-10(-4) M) On isolated guinea pig bronchiolar ring segments precontracted 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 potencies was salbutamol > NKH477 > forskolin (7.3 +/- 0.3, 6.4 +/- 0.3, and 5.4 +/- 0.1, respectively). The bronchodilator effects of salbutamol, isoprenaline, NKH477, and forskolin (10(-9)-10(-4) M) were examined on isolated ovine bronchioles precontracted with carbachol (0.3 muM). Isoprenaline, NKH477, and forskolin produced a concentration-dependent relaxation with pot values of 6.1 +/- 0.2, 5.4 +/- 0.2, and 5.3 +/- 0.2, respectively. Tachyphylaxis to the relaxant effects of salbutamol on guinea pig isolated bronchioles 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 forskolin (10(-6) M) produced a partial reversal of tachyphylaxis to salbutamol-induced relaxation using salbutamol pretreated tissues. The potency of salbutamol was increased to 6.6 +/- 0.2 and 5.9 +/- 0.2 after incubation with NKH477 or forskolin (10(-6) M), respectively Tachyphylaxis to the relaxant effects of isoprenaline resulted in a reduced potency of 5.7 +/- 0.2. Forskolin (10-6 M) Produced a partial reversal of tachyphylaxis, while NKH477 (10(-6) M) produced a complete reversal of tachyphylaxis to isoprenaline-induced relaxation with an pot value of 6.3 +/- 0.1. In conclusion, the guinea pig and sheep isolated bronchioles serve as good models to study the relaxant effects of the bronchodilator agents salbutamol, isoprenaline, NKH477, and forskolin. The beta -agonists examined had higher potencies than NKH477 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. Furthermore, 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 asthma therapy. Drug Dev. Res. 51:169-176, 2000. (C) 2001 Wiley-Liss, Inc.
Place, publisher, year, edition, pages
2000. Vol. 51, no 3, 169-176 p.
NKH477, forskolin, cyclic AMP, tachyphylaxis, salbutamol, bronchioles
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-49396OAI: oai:DiVA.org:liu-49396DiVA: diva2:270292