Study of some physiological mechanisms mediating the cytoprotective effect of clarithromycin on induced gastric mucosal injury in rats

Objective: Helicobacter pylori is the main cause of gastritis, gastroduodenal ulcer and gastric cancer and should be considered as a major public health issue. According to several international guidelines first line therapy for treating Helicobacter pylori infection consists of the usage of macrolide antibiotic (clarithromycin) in combination with other anti secretory agents which has shown to be related to eradication of the microorganism. Although clarithromycin, has been used successfully with antiulcer agents to prolong duodenal ulcer remission it is not well known if it possess cytoprotective effects as well. The aim of the present study was to examine whether clarithromycin may have gastroprotective effect against 96% ethanol induced gastric lesion in rats and to elucidate the role played by opiate receptors, afferent sensory nerve fibers,  and -adrenoceptores, endogeneous prostaglandins, sulfhydryls, fluid volume and mucous volume retained in the gastric lumen, in the mechanism of protection offered by intragastric clarithromycin against ethanol-induced mucosal injury. Methods: Gastric mucosal lesions were induced by 96% ethanol in rats, then the effect of intragastric clarithromycin (in a doserange: 50-400 mg/kg b.wt.) on the ethanol-induced lesion was studied. The effect of blochage of opiate receptors was studied using opiate receptor blocking agent naloxone (8 mg/kg.b.wt. intraperitoneal),denervation of the sensory afferent nerves was done by usage of capsaicin (125 mg/kg b. wt. Subcutaneous),the effect of  adrenergic receptor was done by using 1 adrenergic receptor antagonist prazosin (0.5 mg/kg b. wt. subcutaneous), while the effect of  2 adrenergic receptor was examined by usage of  2 adrenergic receptor antagonist yohimbine (5 mg/kg b. wt. subcutaneous), the influence of 1 adrenoceptores was tested by using 1 adrenoceptores antagonist metoprolol (2 mg/kg b. wt. intraperitoneal), while the effect of  2 adrenoceptores was done by using of  2 adrenoceptores bloker butoxamine (4 mg/kg b. wt. intraperitoneal), the effect of endogenous prostaglandins was assassed by application of cycloxygenase inhibitor indomethacin (5mg/kg b. wt. subcutaneous) and sulphhydryls blocking agent is used (iodoacetamide) in a dose of (100 mg/kg. b.wt. subcutaneous). In addition, the effect of clarithromycin on the volume of gastric content was also investigated. Each study was carried out using six rats per group. Results: It has been found that intragastric administration of clarithromycin protected the rat gastric mucosa against 96% ethanol-induced lesion in a dose dependent manner. The inhibition of lesions was 31.86, 51.33, 79.65 and Bull. Egypt. Soc. Physiol. Sci. 26 (2) 2006 Hala & Safaa et al. 110 91.15% at doses of 50, 100, 200 and 400 mg/kg b.wt. respectively. The gastroprotective effect of clarithromycin was not significantly modified by pretreatment with either opiate receptor blocking agent; or sensory nerve fiber denervation. Subcutaneous pretreatment of rats with 1 blocker or intraperitoneal pretreatment with 1 or 2 blocker did not significantly modify the gastroprotective effect of clarithromycin, however, clarithromycin protection was significantly diminished, although not completely abolished by subcutaneous  2 blocking agent. Clarithromycin protection was not significantly modified by pretreatment with either subcutaneous cycloxygense inhibitor, or sulfhydrls blocker. In addition there was a dose dependent increase in fluid volume for clarithromycin and in the mucous volume at 100, 200 and 400 mg/kg b. wt. of clarithromycin at 30 min.  2 blocking agent significantly reduced both basal and clarithomycin-stimulated gastric mucous secretion. Conclusion: It could be concluded that the mechanism mediating the intragastric clarithromycin protective effect against 96% ethanol induced mucosal lesion is independent of opiate receptors, capsaicin-sensitive afferent sensory nerve fibers, 1, 1-,2-adrenoceptors, endogenous prostaglandins, and sulfhydryl compounds of the gastric mucosa. However, the increase in luminal gastric mucous and fluid volume may contribute to the protective effect of intragastric clarithromycin against 96% ethanol-induced gastric lesion, 2-adrenoceptors possibly are involved in such protection by a mucous dependent mechanism.