Department of Pulmonary Rehabilitation, San Raffaele Pisana Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
J Pharmacol Exp Ther. 2013 Sep;346(3):414-23. doi: 10.1124/jpet.113.204644. Epub 2013 Jun 13.
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.
磷酸二酯酶（PDE）酶家族水解 cAMP 和 cGMP，这是调节多种细胞过程的第二信使，包括气道平滑肌（ASM）松弛和抑制炎症细胞。我们研究了 RPL554[9,10-二甲氧基-2（2,4,6-三甲基苯亚氨基）-3-（N-氨甲酰-2-氨基乙基）-3,4,6,7-四氢-2H-嘧啶并[6,1-a]异喹啉-4-酮]的活性，这是一种双重 PDE3/PDE4 抑制剂，对人离体 ASM 的张力具有双功能作用，以及与毒蕈碱受体拮抗剂或β2-激动剂的任何潜在协同相互作用。我们评估了 RPL554 对人离体支气管中电刺激（EFS）、乙酰胆碱（ACh）或组胺诱导的收缩反应的影响。我们还通过使用 Berenbaum Bliss 独立性（BI）或剂量等效方法，分析了 RPL554 与阿托品、格隆溴铵或沙丁胺醇联合使用的潜在协同作用。RPL554 抑制 EFS 诱导的收缩[最大效力（Emax）91.33 ± 3.37%，P < 0.001]，松弛预先用 ACh 收缩的支气管（Emax 94.62 ± 2.63%，pD2 4.84 ± 0.12，P < 0.001），并消除组胺诱导的收缩。相互作用分析表明，RPL554 与沙丁胺醇之间存在弱协同作用（相互作用指数：0.25 ± 0.06；BIΔ效应：0.29 ± 0.11；剂量等效：无协同作用），但与阿托品（相互作用指数：0.09 ± 0.07；BIΔ效应：0.54 ± 0.09；剂量等效：低浓度时协同作用）或格隆溴铵（ACh：BIΔ效应 0.46 ± 0.03，BerenbaumΔ效应 0.42 ± 0.02；组胺：BIΔ效应 0.46 ± 0.03，BerenbaumΔ效应 0.42 ± 0.03）之间存在显著协同作用。本研究表明，RPL554 舒张人支气管，并可与毒蕈碱受体拮抗剂相互作用，产生对 ASM 张力的协同抑制作用。这些结果表明，RPL554 可能为气道疾病的治疗提供一种新的选择，无论是单独使用还是与抗毒蕈碱药物联合使用。
