Inhibitors of cAMP‐phosphodiesterase 4 (PDE4) exert a number of promising therapeutic benefits, but adverse effects, in particular emesis and nausea, have curbed their clinical utility. Here, we show that PAN‐selective inhibition of PDE4, but not inhibition of PDE3, causes a time‐ and dose‐dependent accumulation of chow in the stomachs of mice fed ad libitum without changing the animals' food intake or the weight of their intestines, suggesting that PDE4 inhibition impairs gastric emptying. Indeed, PDE4 inhibition induced gastric retention in an acute model of gastric motility that traces the passage of a food bolus through the stomach over a 30 minutes time period. In humans, abnormal gastric retention of food is known as gastroparesis, a syndrome predominated by nausea (>90% of cases) and vomiting (>80% of cases). We thus explored the abnormal gastric retention induced by PDE4 inhibition in mice under the premise that it may represent a useful correlate of emesis and nausea. Delayed gastric emptying was produced by structurally distinct PAN‐PDE4 inhibitors including Rolipram, Piclamilast, Roflumilast, and RS25344, suggesting that it is a class effect. PDE4 inhibitors induced gastric retention at similar or below doses commonly used to induce therapeutic benefits (e.g., 0.04 mg/kg Rolipram), thus mirroring the narrow therapeutic window of PDE4 inhibitors in humans. YM976, a PAN‐PDE4 inhibitor that does not efficiently cross the blood‐brain barrier, induced gastroparesis only at significantly higher doses (≥1 mg/kg). This suggests that PDE4 inhibition may act in part through effects on the autonomic nervous system regulation of gastric emptying and that PDE4 inhibitors that are not brain‐penetrant may have an improved safety profile. The PDE4 family comprises four subtypes, PDE4A, B, C, and D. Selective ablation of any of these subtypes in mice did not induce gastroparesis per se, nor did it protect from PAN‐PDE4 inhibitor‐induced gastroparesis, indicating that gastric retention may result from the concurrent inhibition of multiple PDE4s. Thus, potentially, any of the four PDE4 subtypes may be targeted individually for therapeutic benefits without inducing nausea or emesis. Acute gastric retention induced by PDE4 inhibition is alleviated by treatment with the widely used prokinetic Metoclopramide, suggesting a potential of this drug to alleviate the side effects of PDE4 inhibitors. Finally, given that the cause of gastroparesis remains largely idiopathic, our findings open the possibility that a physiologic or pathophysiologic downregulation of PDE4 activity/expression may be causative in a subset of patients.

中文翻译：

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PAN 选择性抑制 cAMP-磷酸二酯酶 4 (PDE4) 诱导小鼠胃轻瘫

cAMP-磷酸二酯酶 4 (PDE4) 抑制剂发挥了许多有希望的治疗效果，但副作用，特别是呕吐和恶心，限制了它们的临床应用。在这里，我们展示了 PDE4 的 PAN 选择性抑制，而不是 PDE3 的抑制，导致在不改变动物的食物摄入量或肠道重量的情况下随意喂养的小鼠胃中食物的时间和剂量依赖性积累，表明 PDE4 抑制会损害胃排空。事实上，在胃动力的急性模型中，PDE4 抑制诱导了胃潴留，该模型追踪食物丸在 30 分钟的时间段内通过胃的过程。在人类中，食物的异常胃潴留被称为胃轻瘫，这是一种以恶心（> 90% 的病例）和呕吐（> 80% 的病例）为主的综合征。因此，我们探索了 PDE4 抑制在小鼠中引起的异常胃潴留，前提是它可能代表呕吐和恶心的有用关联。延迟胃排空是由结构不同的 PAN-PDE4 抑制剂产生的，包括咯利普兰、匹克司特、罗氟司特和 RS25344，表明它是一类效应。PDE4 抑制剂在类似或低于通常用于诱导治疗益处的剂量（例如，0.04 mg/kg 咯利普兰）时诱导胃潴留，因此反映了 PDE4 抑制剂在人类中的狭窄治疗窗。YM976 是一种不能有效穿过血脑屏障的 PAN-PDE4 抑制剂，仅在显着更高的剂量（≥1 mg/kg）时才会诱发胃轻瘫。这表明 PDE4 抑制可能部分通过对胃排空的自主神经系统调节的影响起作用，并且非脑渗透性的 PDE4 抑制剂可能具有更高的安全性。PDE4 家族包括四个亚型，PDE4A、B、C 和 D。在小鼠中选择性消融这些亚型中的任何一个都不会诱导胃轻瘫本身，也不能防止 PAN-PDE4 抑制剂诱导的胃轻瘫，表明胃潴留可能由多个 PDE4 的同时抑制引起。因此，潜在地，四种 PDE4 亚型中的任何一种都可以单独靶向治疗，而不会引起恶心或呕吐。由 PDE4 抑制引起的急性胃潴留可通过广泛使用的促动力甲氧氯普胺治疗缓解，表明该药物具有减轻 PDE4 抑制剂副作用的潜力。最后，鉴于胃轻瘫的病因在很大程度上仍然是特发性的，我们的研究结果表明，PDE4 活性/表达的生理或病理生理下调可能是一部分患者的病因。