Both α2B- and α2C-adrenoceptor subtypes are involved in the mediation of centrally induced gastroprotection in mice

Abstract

α(2)-adrenoceptors are known to mediate gastroprotective effect in both acid-dependent and acid-independent ulcer models. The aim of the present study was to determine, which of the three α(2)-adrenoceptor subtypes (α(2A), α(2B) or α(2C)) is responsible for this protection. Various α(2)-adrenoceptor agonists and antagonists were administered intracerebroventricularly (i.c.v.) to C57BL/6 mice with deletion of genes encoding the different subtypes. The gastric mucosal damage was induced by orally injected acidified ethanol. Both the non-selective α(2)-adrenoceptor agonist clonidine (0.3-2.8 nmol) and the α(2B/C)-adrenoceptor subtype preferring agonist ST-91 (0.5-11.5 nmol) induced dose-dependent gastroprotective effect in wild type, α(2A)-, α(2B)- and α(2C)-KO mice. In contrast, the α(2A)-adrenoceptor subtype agonist oxymetazoline (0.07-84 nmol i.c.v.) reduced only slightly the development of ethanol-induced ulcers. The effect of clonidine was antagonized by the non-selective antagonist yohimbine (25 nmol) and the α(2B/C)-adrenoceptor antagonist ARC 239 (10.4 nmol), but not by the α(2A)-adrenoceptor antagonist BRL 44408 (7.5 nmol). ARC 239 also reversed the effect of clonidine in α(2A)-, α(2B)- and α(2C)-KO mice, while the selective α(2C)-adrenoceptor antagonist JP 1302 (52 nmol) antagonized that only in α(2B)-KO, but not in α(2A)- and α(2C)-KO mice. These results suggest that α(2B)- and α(2C)-adrenoceptor subtypes can equally contribute to the mediation of gastroprotective effect induced by α(2)-adrenoceptor agonists in mice.