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

Background and PurposeWe investigated the effectiveness of RPL554, a dual PDE3 and 4 enzyme inhibitor, on airway smooth muscle relaxation and compared it with that induced by salbutamol, ipratropium bromide, glycopyrrolate or their combination on bronchomotor tone induced by different spasmogenic agents. Experimental ApproachGuinea pig tracheal preparations were suspended under 1g tension in Krebs-Henseleit solution maintained at 37 degrees C and aerated with 95% O-2/5% CO2 and incubated in the presence of indomethacin (5M). Relaxation induced by cumulative concentrations of muscarinic receptor antagonists (ipratropium bromide or glycopyrrolate), (2)-adrenoceptor agonists (salbutamol or formoterol), PDE3 inhibitors (cilostamide, cilostazol or siguazodan) or a PDE4 inhibitor (roflumilast) was evaluated in comparison with RPL554. Maximal relaxation was calculated (% Emax papaverine) and expressed as meanSEM. Key ResultsBronchomotor tone induced by the various spasmogens was reduced by the different bronchodilators to varying degrees. RPL554 (10-300M) caused near maximum relaxation irrespective of the spasmogen examined, whereas the efficacy of the other relaxant agents varied according to the contractile stimulus used. During the evaluation of potential synergistic interactions between bronchodilators, RPL554 proved superior to salbutamol when either was combined with muscarinic receptor antagonists. Conclusions and implicationsRPL554 produced near maximal relaxation of highly contracted respiratory smooth muscle and provided 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.