In vivo characterization of 5-HT1A receptor-mediated gastric relaxation in conscious dogs

Abstract

Accumulating data have been published emphasizing the important role of 5-hydroxytryptamine (5-HT) receptors in proximal stomach relaxation. However, a proper in vivo characterization of 5-HT receptors mediating gastric relaxation is still missing. In the current study, we focus on the in vivo characterization of 5-HT1A receptors mediating relaxation of the proximal stomach in conscious dogs. Beagle dogs were equipped with a gastric fistula. In the conscious state, volume changes within an intragastric bag were measured at constant pressure by means of a barostat. Results are presented as the maximum volume increase after treatment (mean+/-s.e.m.). All drugs were injected intravenously. The 5-HT1A receptor agonist flesinoxan (10, 50, 100 and 150 microg kg-1) induced a dose-dependent relaxation of the canine proximal stomach (50+/-10, 230+/-51, 290+/-38 and 275+/-33 ml, respectively; n=9-11). The selective 5-HT1A receptor antagonist WAY-100635 dose-dependently inhibited the flesinoxan-induced relaxation. NG-nitro-l-arginine methyl ester did not affect this relaxation, suggesting that nitrergic nerves are not involved. After supradiaphragmatic vagotomy, the baseline of the intragastric volume was larger compared to that before vagotomy (317+/-50 vs 142+/-28 ml, respectively; n=5). Compensation for this by either reduction of the intraballoon pressure or infusion of a contractile dose of bethanechol did not establish a condition in which flesinoxan was able to relax the stomach. In contrast, nitroprusside induced a significant gastric relaxation when tone was increased by bethanechol. It is concluded that flesinoxan induces proximal gastric relaxation in conscious dogs via 5-HT1A receptors. The response is mediated through a vagal pathway without involvement of nitrergic nerves.

Figure 1

Mean barostat recordings of canine intragastric volume (at 6 mmHg intrabag pressure). All curves are shown after subtraction of the mean baseline volume. (a) Dose–response curves of flesinoxan (n=9–11; i.v.). (b) Influence of flesinoxan, nitroprusside and saline after vagotomy (n=5; i.v.). In order to obtain a comparable baseline volume as before vagotomy, a bethanechol infusion was applied (condition 3).

Figure 2

Maximal intragastric volume increase induced by 100 μg kg⁻¹ flesinoxan (i.v.) after pretreatment with saline or different doses of WAY-100635 (WAY; i.v.). Intragastric volumes shown as mean±s.e.m.; n=6 ^*P<0.05, ^**P<0.01, ^***P<0.0001 compared to saline addition.