Analysis of α2-adrenoceptor subtypes involved in the regulation of gastroprotection and gastric motility in mice

Introduction:α2-Adrenoceptors (α2-AR) regulate several gastrointestinal functions. In the last decades three α2-AR subtypes have been identified. The present study aimed to characterize, which α2-AR subtypes mediate the effects of α2-agonists on the gastric motility and mucosal defense in mice. Experiments were carried out with different subtype selective agonists and antagonists, and, on the other hand, with genetically engineered mice. Methods: NMRI mice and C57/BL6 mice with a deletion of the α2-AR subtypes (KO-mice) were used. 1. The gastroprotective effect of the α2-agonists was investigated on the ethanol ulcer model (0.5ml acidified ethanol per os), and the drugs were injected intracerebroventricularly (i.c.v.). 2. Gastric motor activity was measured in vitro. Contractions of the fundus strips were evoked by electrical field stimulation (EFS) and α2-agonists were injected into the organ bath in a cumulative manner. Results: 1. α2-AR agonists clonidine (0.95 nmol) and ST-91 (11 nmol) reduced significantly the ethanol-induced mucosal damage in wild type, α2A- and α2C-KO mice. The effect of clonidine was antagonized by the non-selective α2-antagonist yohimbine and the α2B/C-selective antagonist ARC-239. 2. Clonidine and ST-91 (1–1000 nM) dose-dependently inhibited the EFS-induced gastric contractions in NMRI mice, which could be inhibited by the non-selective α2-antagonist idazoxan and the α2A-antagonist BRL-44408, however, it was not affected by ARC-239. Furthermore, clonidine and ST-91 inhibited gastric contractions in wild type, α2B-KO and α2C-KO mice, but not in α2A-KO mice. Conclusions: Based on these results the α2A-subtype may regulate the gastric motor activity, while α2nonA/nonC, presumably the α2B-subtype may be responsible for the gastroprotective effect. Identifying the subtypes responsible for the different effects may lead to the development of more selective drugs, with less side effects.

The work was supported by ETT 341/2009 from the Scientific Health Council and National Office for Research and Technology (NKTH).