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


METHODS
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.


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
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.
De Maeyer
J H
JH
Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium. demaeyer@movetis.com
Schuurkes
J A J
JA
Lefebvre
R A
RA
D000818:Animals; D016279:Atrial Function, Left / Q000187:drug effects; D001572:Benzofurans / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D008954:Models, Biological; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects*; D009928:Organ Specificity; D044422:Receptors, Serotonin, 5-HT4 / Q000502:physiology; D058828:Serotonin 5-HT4 Receptor Agonists; D058832:Serotonin 5-HT4 Receptor Antagonists; D013270:Stomach / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D013552:Swine; D009435:Synaptic Transmission; D013618:Tachyphylaxis
D001572:Benzofurans; D058828:Serotonin 5-HT4 Receptor Agonists; D058832:Serotonin 5-HT4 Receptor Antagonists; C406662:prucalopride; D044422:Receptors, Serotonin, 5-HT4