Novel relaxant effects of RPL554 on guinea-pig tracheal smooth muscle contractility

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Abstract

Background and Purpose:

We investigated the effectiveness of RPL554 a dual phosphodiesterase 3 and 4 enzyme inhibitor, on airway smooth muscle relaxation and compared it to that induced by salbutamol, ipratropium bromide, glycopyrrolate or their combination on bronchomotor tone induced by different spasmogenic agents.

Experimental Approach:

Guinea-pig tracheal preparations were suspended under 1 g tension in Krebs Henseleit solution maintained at 37 °C and aerated with 95% O2/5% CO2 and incubated in the presence of indomethacin (5 μM). Relaxation induced by cumulative concentrations of muscarinic receptor antagonists (ipratropium bromide or glycopyrrolate), beta2-agonists (salbutamol or formoterol), a PDE3 inhibitor (cilostamide, cilostazol or siguazodan) or a PDE4 inhibitor (roflumilast) was evaluated in comparison with RPL554. Maximal relaxation was calculated (% Emax papaverine) and expressed as mean ± sem.

Key Results:

Bronchomotor tone induced by the various spasmogens was reduced by the different bronchodilators to varying degrees. RPL554 (10-300 M) caused near maximum relaxation irrespective of the spasmogen examined, whereas the efficacy of the other relaxant agents varied according to the contractile stimulus used. In further studies to evaluate potential synergistic interaction between bronchodilators, RPL554 proved superior to salbutamol when either was combined with muscarinic receptor antagonists.

Conclusions and implications:

RPL554 produces near maximal relaxation of highly contracted respiratory smooth muscle and provides additional relaxation compared with that produced by other clinically used bronchodilator drugs. This suggests that RPL554 has the potential to produce additional beneficial bronchodilation over and above that of maximal clinical doses of standard bronchodilators in highly constricted airways of patients.

Original languageEnglish
JournalBritish Journal of Pharmacology
Volume173
Issue number15
Early online date7 Jul 2016
DOIs
Publication statusPublished - Aug 2016

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