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NEUROREGULATION AND MOTILITY

Characterization of 5-HT₇-receptor-mediated gastric relaxation in conscious dogs

¹Heymans Institute of Pharmacology, Ghent University, Ghent; and ²Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium

Submitted 11 January 2005 ; accepted in final form 28 February 2005

We aimed to evaluate the gastric relaxant capacity of the 5-HT_1/7-receptor agonist 5-carboxamidotryptamine (5-CT) in conscious dogs and to clarify the mechanism of action by use of selective antagonists, vagotomy, and in vitro experiments. A barostat enabled us to monitor the intragastric volume in response to different treatments (intravenously administered) before and after supradiaphragmatic vagotomy [results presented as the maximum volume change after treatment (mean; n = 5–11)]. In vitro experiments were performed with isolated muscle strips cut from four different stomach regions of the vagotomized dogs [results were fitted to the operational model of agonism to determine the efficacy parameter (n = 5)]. 5-CT (0.5–10 µg/kg) caused a dose-dependent gastric relaxation (29–267 ml) that was completely blocked by the selective 5-HT₇-receptor antagonist SB-269970 (50 µg/kg). After vagotomy, the relaxation to 10 µg/kg 5-CT was significantly less pronounced (73 vs. 267 ml; P < 0.05) but still blocked by SB-269970, whereas the response to the nitric oxide donor nitroprusside was similar to that before vagotomy (178 vs. 218 ml). In vitro, 5-CT concentration dependently inhibited the PGF₂-contracted muscle strips before and after vagotomy. Although before and after vagotomy the response in every region was mediated by 5-HT₇ receptors (apparent affinity dissociation constant: SB-269970, 8.2–8.6 vs. 8.3–8.6, respectively), the response after vagotomy was less efficacious (log : 1.9 to 0.5 vs. 1.4 to –0.1). The results indicate that the 5-CT-induced proximal stomach relaxation in conscious dogs before and after vagotomy is mediated via 5-HT₇ receptors. The decreased efficacy of 5-CT in vitro after vagotomy is probably related to vagotomy-induced changes in receptor density or coupling efficiency and provides a possible explanation for the decreased in vivo response to 5-CT after vagotomy.

5-HT₇; efficacy distribution; vagotomy; barostat