Aims: Besides acting as gastrointestinal prokinetic agents, 5-hydroxytryptamine 4 (5-HT 4) receptor agonists can induce positive inotropism in human isolated atrium, but not in ventricles. We pharmacologically evaluated the gastroprokinetic 5-HT 4 receptor agonists tegaserod, prucalopride, R199715, cisapride, the cisapride metabolite norcisapride, and the 5-HT 3 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-HT 4 receptor antagonist GR113808. Partial agonism was assessed using 5-HT 4 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, tegaserod and R199715, but not MKC-773. 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-HT 4 receptor agonists, while prucalopride, norcisapride and MKC-733 cause no significant effects on human atrial trabeculae, (iii) R199715 seems to behave as a 5-HT 4 receptor antagonist.

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Life Sciences
Department of Virology

Chai, W, Chan, K.Y, de Vries, R.R.P, van den Bogeardt, A.J, de Maeyer, J.H, Schuurkes, J.A.J, … Maassen van den Brink, A. (2012). Inotropic effects of prokinetic agents with 5-HT 4 receptor agonist actions on human isolated myocardial trabeculae. Life Sciences (Vol. 90, pp. 538–544). doi:10.1016/j.lfs.2012.01.009