Selective desensitization of the 5-HT4 receptor-mediated response in pig atrium but not in stomach
Selective desensitization of the 5-HT4 receptor-mediated response in pig atrium but not in stomach
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DOI：
10.1111/j.1476-5381.2008.00007.x
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发表时间：
2009-01-01
影响因子：
7.3
通讯作者：
Lefebvre, R. A.
中科院分区：
文献类型：
--
作者：
De Maeyer, J. H.;Schuurkes, J. A. J.;Lefebvre, R. A.
5-HT 4受体激动剂的作用的时间依赖性取决于许多特定的调节机制，这些机制在组织之间变化。这对于内源性5-HT的作用以及5-HT 4受体激动剂的临床应用具有重要意义，并且可能有助于激动剂的组织选择性。胃胆碱能神经传递和心房收缩性。胃组织暴露于5-HT或选择性5-HT 4受体激动剂普卢卡必利和M0003导致暴露期间持续的非瞬时效应;洗脱后，对随后的5-HT激发的反应没有显示明显的脱敏。孵育左心房组织与5-HT导致在一个短暂的反应，导致冲洗后的后续反应显着脱敏5-HT。选择性5-HT_4受体激动剂普卢卡必利和M0003仅诱导非常弱的心房反应，而它们在使心房对5-HT的反应脱敏方面非常有效。观察结果还表明，普卢卡必利和M0003结合和/或激活5-HT 4受体的特性与5-HT不同。普卢卡必利和M0003对5-HT脱敏的高效力以及它们在心房中的低效力强调了这类5-HT 4受体激动剂的心脏安全性。
The time dependency of the effect of 5-HT4 receptor agonists depends on many specific regulatory mechanisms, which vary between tissues. This has important implications with regard to the effects of endogenous 5-HT, as well as to the clinical use of 5-HT4 receptor agonists, and might contribute to tissue selectivity of agonists.The progression and desensitization of 5-HT4 receptor-mediated responses were evaluated in an organ bath set-up using two, clinically relevant, porcine in vitro models: gastric cholinergic neurotransmission and atrial contractility.Exposure of gastric tissue to 5-HT or to the selective 5-HT4 receptor agonists prucalopride and M0003 results in a sustained non-transient effect during exposure; after washout, the response to a subsequent challenge with 5-HT shows no clear desensitization. Incubation of left atrial tissue with 5-HT resulted in a transient response, leading after washout to a marked desensitization of the subsequent response to 5-HT. The selective 5-HT4 receptor agonists prucalopride and M0003 induce only very weak atrial responses whereas they are very effective in desensitizing the atrial response to 5-HT. The observations also suggest that the properties of prucalopride and M0003 to bind to and/or activate the 5-HT4 receptor differ from those of 5-HT. This difference might have contributed to the observed desensitization.The high potency of prucalopride and M0003 in desensitizing the response to 5-HT together with their low efficacy in the atrium emphasizes the cardiac safety of this class of 5-HT4 receptor agonists.