I1-imidazoline receptor/α2-adrenoceptor mediated gastroprotection

Introduction: Rilmenidine is a widely used centrally acting antihypertensive agent. Its antihypertensive action is due to stimulation of central I1-imidazoline receptor/α2-adrenoceptor. Since our previous experiments showed that activation of central α2-adrenoceptors resulted in gastroprotective effect against different types of gastric mucosal damage we aimed to examine the effect of rilmenidine on experimental gastric ulcer.

Methods: Gastric damage was induced by ethanol. Rilmenidine was injected either intraperitoneally (ip.) or intracerebroventricularly (icv.) 20 and 10min resp., before the ethanol challenge. The degree of gastric damage was estimated macroscopically and characterised by ulcer index (calculated form the number and severity of gastric mucosal lesion). Gastric acid secretion was measured in pylorus ligated rats, the volume and acidity was measured 4h after ligation. The antagonists were injected icv. 10min before rilmenidine administration.

Results: Rilmenidine inhibited the ethenol-induced lesion given ip. (ED50: 2 nmol/kg) or icv. (ED50: 0.006 nmol/rat). In both cases the dose-response curves proved to be bell-shaped. Involvement of alpha-2 adrenoceptors was suggested by the antagonistic effect of yohimbine (50 nmol/rat icv.) as well as prazosin (5 nmol/rat icv.) and ARC 239 (50 nmol/rat icv.) (alpha-2B adrenoceptor antagonists). The involvement of endogenous opioid system was suggested by the findings that both naloxone (5 nmol/rat icv.; µ-antagonist), naltrindole (5 nmol/rat icv. δ-antagonist) and norbinaltorphimine (27 nmol/rat icv.; κ-opioid receptor antagonists) highly reduced the gastro-protective effect of rilmenidine. Furthermore, rilmenidine even in the dose of 210 nmol/rat icv. failed to affect gastric acid secretion.

Conclusion: The centrally acting antihypertensive agent rilmenidine induces gastric mucosal protection. The gastroprotective dose range (2–10 nmol/rat ip) is far below its antihypertensive one (200–400 nmol/kg iv). The centrally-induced protective effect involves activation of α2B-adrenoecptor subtypes as well as opioid system. It might be raised that antihypertensive therapy with rilmenidine may exert beneficial action on gastric mucosa – though further studies are needed in human beings to demonstrate the mucosal protective effect of rilmenidine.

The work was supported by grant ETT 389/2003.