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Inotropic Effects of Prokinetic Agents With 5-HT(4) Receptor Agonist Actions on Human Isolated Myocardial Trabeculae

Inotropic Effects of Prokinetic Agents With 5-HT(4) Receptor Agonist Actions on Human Isolated Myocardial Trabeculae

Wenxia Chai, Kayi Y Chan, René de Vries, Antoon J van den Bogeardt, Joris H de Maeyer, Jan A J Schuurkes, Carlos M Villalón, Pramod R Saxena, A H Jan Danser, Antoinette MaassenVanDenBrink

Life Sci. 2012 Apr 9;90(13-14):538-44.

PMID: 22326501

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP194093420	MKC-733		194093-42-0	Price

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