The dual PDE3/PDE4 phosphodiesterase inhibitor RPL554 produces more complete bronchodilator responses than the beta2-agonist salbutamol and the anti-muscarinic agent ipratropium bromide, alone and in combination, in guinea-pig isolated trachea

Introduction: RPL554 causes clinically effective bronchodilation in asthma and COPD (Franciosi, L.G et al. Lancet Respir Med 2013; 1:714-727) by relaxation of human airway smooth muscle (Calzetta, L et al. J Pharmacol Exp Ther 2013; 346:414-423). Aims: To investigate whether RPL554 provides additional functional antagonism to relaxant agonists against bronchomotor tone induced by different spasmogens. Methods: Bronchomotor tone in guinea-pig isolated trachea was elicited by carbachol/histamine (10 µM each) in the absence or presence of LTC4 (100 nM) or K + ions (40 mM) and carbachol (10 µM) followed by relaxation to ipratropium bromide (IB), salbutamol (SALB) alone, in combination (1:5.7, respectively, and referred to as Combivent); glycopyrrolate (GLY); and RPL554. Maximal relaxation (% Emax papaverine) expressed as mean±sem (N=3-6 animals). Results: In tissues contracted with carbachol/histamine, only IB failed to fully reverse bronchomotor tone (75±5 %). In tissues contracted with LTC4/histamine/carbachol the response to these agents differed (IB, 69±9; SALB, 72±6; 9combivent9, 95±3, GLY, 62±4, and RPL554, 97±1). Tissues contracted with potassium ions u0026 carbachol were more resistant to these agents (IB, 73±6; SALB, 48±8; Combivent, 82±4, RPL554, 90±5). RPL554 provided additional relaxation when bronchodilator drugs did not achieve maximum relaxation in this preparation. Conclusion . RPL554 has the clinical potential to produce additional bronchodilation over and above that of standard bronchodilators in highly constricted airways.