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Br J Pharmacol. 2009 Jan;156(2):362-76. doi: 10.1111/j.1476-5381.2008.00007.x. Epub 2009 Jan 13.

Selective desensitization of the 5-HT4 receptor-mediated response in pig atrium but not in stomach.

Author information

1
Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium. demaeyer@movetis.com

Abstract

BACKGROUND AND PURPOSE:

The time dependency of the effect of 5-HT(4) 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-HT(4) receptor agonists, and might contribute to tissue selectivity of agonists.

EXPERIMENTAL APPROACH:

The progression and desensitization of 5-HT(4) 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.

KEY RESULTS:

Exposure of gastric tissue to 5-HT or to the selective 5-HT(4) 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-HT(4) 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-HT(4) receptor differ from those of 5-HT. This difference might have contributed to the observed desensitization.

CONCLUSIONS AND IMPLICATIONS:

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-HT(4) receptor agonists.

PMID:
19154432
PMCID:
PMC2697841
DOI:
10.1111/j.1476-5381.2008.00007.x
[Indexed for MEDLINE]
Free PMC Article

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