Effect of the Mixed Phosphodiesterase 3/4 Inhibitor RPL554 on Human Isolated Bronchial Smooth Muscle Tone

Abstract

The phosphodiesterase (PDE) enzyme family hydrolyzes cAMP and cGMP, second messengers that regulate a variety of cellular processes, including airway smooth muscle (ASM) relaxation and the inhibition of inflammatory cells. We investigated the activity of RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(n-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one], a dual PDE3/PDE4 inhibitor that exhibits bifunctional activity for its effects on the tone of human isolated ASM and any potential synergistic interactions with muscarinic receptor antagonists or a β2-agonist. We evaluated the influence of RPL554 on the contractile response induced by electrical field stimulation (EFS), acetylcholine (ACh), or histamine on human isolated bronchi. We also analyzed the potential synergistic effect of RPL554 in combination with atropine, glycopyrollate, or salbutamol by using the Berenbaum Bliss Independence (BI), or the dose equivalence methods. RPL554 inhibited the contraction induced by EFS [maximal effectiveness (Emax) 91.33 ± 3.37%, P < 0.001], relaxed bronchi precontracted with ACh (Emax 94.62 ± 2.63%, pD2 4.84 ± 0.12, P < 0.001), and abolished the contraction induced by histamine. Analysis of interactions indicated a weak synergism between RPL554 and salbutamol (interaction index: 0.25 ± 0.06; BI Δeffect: 0.29 ± 0.11; dose equivalence: no synergism) but significant synergism between RPL554 and atropine (interaction index: 0.09 ± 0.07; BI Δeffect: 0.54 ± 0.09; dose equivalence: synergism for low concentrations) or glycopyrrolate (ACh: BI Δeffect 0.46 ± 0.03, Berenbaum Δeffect 0.42 ± 0.02; histamine: BI Δeffect 0.46 ± 0.03, Berenbaum Δeffect 0.42 ± 0.03). This study demonstrates that RPL554 relaxes human bronchi and that it can interact with a muscarinic receptor antagonist to produce a synergistic inhibition of ASM tone. These results suggest that RPL554 may provide a novel treatment of airway diseases, either alone or in combination with antimuscarinic drugs.