Inotropic effects of prokinetic agents with 5-HT₄ receptor agonist actions on human isolated myocardial trabeculae

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• 作者：Wenxia Chai^a ; ¹ ; Kayi Y. Chan^a ; ¹ ; ^{k.y.chan@erasmusmc.nl} ; Ren&eacute ; de Vries^a ; Antoon J. van den Bogeardt^b ; Joris H. de Maeyer^c ; Jan A.J. Schuurkes^c ; Carlos M. Villaló ; n^d ; Pramod R. Saxena^a ; A.H. Jan Danser^a ; Antoinette MaassenVanDenBrink^a
• 关键词：Atrium ; Contractility ; Gastrointestinal prokinetic agents ; 5-HT ; 5-HT4 receptors
• 刊名：Life Sciences
• 出版年：2012
• 期刊代码：62_00243205
• 类别：imm
• 出版时间：9 April, 2012
• 卷：90
• 期：13-14
• 页码：538-544
• 文件大小：948 K

摘要

<h4 class="h4">Aimsh4>Besides acting as gastrointestinal prokinetic agents, 5-hydroxytryptamine₄ (5-HT₄) receptor agonists can induce positive inotropism in human isolated atrium, but not in ventricles. We pharmacologically evaluated the gastroprokinetic 5-HT₄ receptor agonists tegaserod, prucalopride, R199715, cisapride, the cisapride metabolite norcisapride, and the 5-HT₃ receptor agonist MKC773 on human isolated myocardial trabeculae, and compared their effects with those induced by 5-HT and 5-methoxytryptamine (5-MeOT).<h4 class="h4">Main methodsh4>

Atrial and ventricular trabeculae were paced and changes in contractile force were studied in the absence or presence of the 5-HT₄ receptor antagonist GR113808. Partial agonism was assessed using 5-HT₄ receptor agonists as antagonists against 5-HT. To test the contribution of L-type calcium channels, the inotropic responses to 5-HT and 5-MeOT were studied in the absence or presence of verapamil.<h4 class="h4">Key findingsh4>

Like 5-HT and 5-MeOT, cisapride and tegaserod, but not prucalopride, R19971 and MKC颅733, induced concentration-dependent positive inotropic responses on atrial trabeculae, which were abolished by GR113808. The L-type calcium channel blocker verapamil attenuated inotropic responses to 5-HT and 5-MeOT. None of the agonists affected the contraction of left ventricular trabeculae. Concentration response curves to 5-HT were shifted to the right in the presence of prucalopride, cisapride, tegaserod and R199715, but not MKC-773.<h4 class="h4">Significanceh4>

We conclude that (i) inotropic responses to 5-HT and 5-MeOT seem to depend on L-type calcium channels, (ii) tegaserod and cisapride behave as partial 5-HT₄ receptor agonists, while prucalopride, norcisapride and MKC-733 cause no significant effects on human atrial trabeculae, (iii) R199715 seems to behave as a 5-HT₄ receptor antagonist.