Aims: 

The imidazoline hypothesis was raised in the middle of 80's and suggests that some effects of clonidine and structurally related a₂-adrenoceptor agonists is mediated by imidazoline receptors, instead of a₂-adrenoceptors. However, analysis of imidazoline receptors can raise several difficulties, since most imidazoline agonists possess reasonable affinity for a₂-adrenoceptors as well. The aim of our study was to test different imidazoline ligands (clonidine, moxonidine, rilmenidine, AGN 192403) in a₂-adrenoceptor-KO mice in order to clarify whether they can inhibit gastric contractions in mice, and if so, a₂-adrenoceptors or imidazoline receptors mediate their effect.

Methods: 

Wild type, a_2A-, a_2B- and a_2C-KO C57BL/6 mice were used. For analysis of gastric motor activity, mice were killed by cervical dislocation, their stomachs were removed and fundus strips were suspended between two electrodes in 5 ml organ baths containing 37°C Krebs solution, then EFS was applied. Drugs were added in a cumulative manner.

Results: 

1) Both moxonidine and rilmenidine (1-10,000 nM) inhibited the EFS-induced contractions in a concentration dependent manner in wild type, a_2B- and a_2C-KO mice. 2) The effect of both drugs was antagonized by the non selective a₂-adrenoceptor and imidazoline antagonist idazoxan (10,000 nM) and by the selective a_2A-adrenoceptor antagonist BRL 44408 (10,000 nM). 3) Neither moxonidine, nor rilmenidine inhibited the gastric contractions in a_2A-KO mice. 4) The selective I1-agonist AGN 192403 (1-10,000 nM) failed to affect the EFS-induced contractions in wild type mice.

Conclusion: 

Our results obtained from genetically engineered mice strongly suggest that a_2A-adrenoceptors, and not imidazoline receptors mediate the inhibitory effect of imidazoline ligands on the gastric motility.

Support: 

ETT 341/2009 from the Scientific Health Council and National Office for Research and Technology (NKTH)