Key result
Prucalopride and M0003 induced weak atrial responses but effectively desensitized the atrial response to 5-HT, whereas they produced sustained non-transient effects in gastric tissue.
Why the study?
Do selective 5-HT4 receptor agonists cause tissue-specific desensitization in porcine atrial versus gastric tissues?
Do selective 5-HT4 receptor agonists cause tissue-specific desensitization in porcine atrial versus gastric tissues?
Selective 5-HT4 receptor agonists prucalopride and M0003 exhibit tissue-selective desensitization, effectively desensitizing atrial responses to 5-HT with low intrinsic efficacy, supporting their cardiac safety.
Animal data suggest cardiac safety of selective 5-HT4 agonists; leaves open translation to human tissues and practice.
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.
No takes yet. Share an insight, caveat, or question.
Maeyer et al. (2009) studied this question. 5-HT4 receptor agonists (prucalopride and M0003) vs. 5-HT was evaluated on Progression and desensitization of 5-HT4 receptor-mediated responses. Prucalopride and M0003 induced weak atrial responses but effectively desensitized the atrial response to 5-HT, whereas they produced sustained non-transient effects in gastric tissue.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: