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NKH477: A novel bronchodilator produces potentiation and tachyphylaxis reversal to salbutamol in isolated guinea pig trachea
Kuwait Univ, Fac Med, Dept Pharmacol & Toxicol, Safat 13110, Kuwait Linkoping Univ, Fac Hlth Sci, S-58183 Linkoping, Sweden.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Physiology .
1999 (English)In: Drug development research (Print), ISSN 0272-4391, E-ISSN 1098-2299, Vol. 48, no 4, 154-159 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
1999. Vol. 48, no 4, 154-159 p.
Keyword [en]
NKH477, cyclic AMP, tachyphylaxis, beta(2)-adrenoceptor agonist, trachea
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-49855OAI: oai:DiVA.org:liu-49855DiVA: diva2:270751
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-12

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Thulesius, Olav

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