Central and peripheral mechanisms involved in the agmatine-induced gastroprotection in the rat

Introduction: In 1994 the biosynthesis of agmatine in mammalian brain has been reported. Agmatine was described as an endogenous ligand of the imidazoline binding sites, however, several data indicates that it can also interact with numerous other receptors, like α2-adrenoceptors, NMDA- or serotonin 5-HT3 receptors. It is widely distributed in the CNS and exerts several central (e.g. antidepressant or anxiolytic) effects. Moreover, agmatine and imidazoline receptors have also been identified in the gastrointestinal tract. Aims: We analysed the effect of centrally injected agmatine on gastric mucosal injury induced by a necrotizing agent. Methods: The ethanol-ulcer model was used. After 24h starvation, male Wistar rats were given 0.5ml acidified ethanol orally. The mucosal lesions were evaluated 1h later. Agmatine was given intracerebroventricularly (i.c.v.) 10min before the ethanol challenge. Antagonists were injected peripherally (s.c., i.v. or per os) or centrally (i.c.v.) before the administration of agmatine. Results: 1. Agmatine induced dose-dependent gastroprotective effect after central (0.044–1.76 nmol/rat i.c.v.) administration. 2. The imidazoline I1 receptor antagonist efaroxan (4 nmol/rat i.c.v.) as well as the non-selective α2-adrenoceptor antagonist yohimbine (5µmol/kg s.c.) antagonized the agmatine-induced mucosal protection. 3. Similarly, the effect of agmatine was abolished after bilateral cervical vagotomy. 4. The nitric oxide synthase inhibitor N(G)-nitro-L-arginine (L-NNA, 13.7µmol/kg i.v.) and the cyclooxigenase inhibitor indomethacin (56 mmol/kg p.os) also reduced the protective effect of agmatine. Conclusions: Agmatine via activation of central imidazoline I1 receptors and α2-adrenoceptors may initiate a chain of events which result in the gastric mucosal protection. The effect is conveyed by the vagal nerve to the periphery, where nitric oxide and prostaglandins may mediate it.