Analysing the effect of imidazoline receptor agonists and antagonists on the gastric motility in mice

Introduction: Both imidazoline receptors and endogenous imidazoline ligands have been identified throughout the gastrointestinal (GI) tract, but their physiological role remains uncertain. On the other hand, functional GI disorders accompanied by motility disturbances (e.g. functional dyspepsia and idiopathic gastroparesis) are common clinical problems and new targets for drug development are needed. The present study was undertaken to clarify, whether the endogeous imidazoline system takes part in the modulation of gastric motility. Methods: Various imidazoline ligands were tested on the electrical field stimulation (EFS)-induced gastric contractions in wild-type (WT) and α2A-adrenoceptor knockout (KO) mice. The latter was necessary because many imidazoline receptor ligands bind to α2-adrenoceptors as well, and among the three α2-adrenoceptor subtypes the α2A-one is predominantly expressed in the GI tract. Results: Clonidine, moxonidine and rilmenidine (mixed α2-adrenoceptor- and I1 receptor agonists) inhibited the EFS-induced gastric contractions in a concentration dependent manner in WT mice, which effect was inhibited by idazoxan (α2-adrenoceptor and I1 receptor antagonist, I2 receptor ligand) and BRL 44408 (α2A-adrenoceptor subtype antagonist), but not by ARC 239 (α2B/C-adrenoceptor subtype antagonist), AGN 192403 (I1 receptor antagonist) and BU 224 (I2 receptor antagonist). Furthermore, the mixed α2-adrenoceptor- and I1 receptor agonists had no or only weak effect in α2A-adrenoceptor KO mice. The endogenous imidazoline receptor ligand agmatine failed to affect the EFS-induced contractions, while harmane (an other endogenous imidazoline receptor ligand) and 2-BFI (a selective imidazoline I2 receptor agonist) exerted a slight effect in both WT and α2A-adrenoceptor KO mice, but this was not reversible by idazoxan, AGN 192403 and BU 224. Conclusions: The inhibitory effect of the tested imidazoline compounds on cholinergic gastric contractions is mediated mainly by α2A-adrenoceptors. Although at higher concentrations other receptors may also contribute to their effects, the lack of inhibition by AGN 192403 and BU 224 suggests that these are not imidazoline I1 and I2 receptors.

This work was supported by the National Development Agency [TÁMOP-4.2.1/B-09/1/KMR-2010] and by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences.