Selective desensitization of the 5‐HT 4 receptor‐mediated response in pig atrium but not in stomach

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.