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

Wenxia Chai, Ka yi Chan, René de Vries, Antoon J. van den Bogeardt, Joris H. de Maeyer, Jan A.J. Schuurkes, Carlos M. Villalon Herrera, Pramod Saxena, Jan Danser, Antoinette Maassen van den Brink

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11 Citations (Scopus)

Abstract

Aims: Besides acting as gastrointestinal prokinetic agents, 5-hydroxytryptamine(4) (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). Main methods: 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. Key findings: Like 5-HT and 5-MeOT, cisapride and tegaserod, but not prucalopride, R19971 and MKC-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 Significance: 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. (C) 2012 Elsevier Inc. All rights reserved.
Original languageEnglish
Pages (from-to)538-544
Number of pages7
JournalLife Sciences
Volume90
Issue number13-14
DOIs
Publication statusPublished - 9 Apr 2012

Research programs

  • EMC COEUR-09

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