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
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.