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Mechanisms of irritative activity of compound 48/80 on rat gastric mucosa
Abstract:
A single intraperitoneal injection of compound 48/80 (48/80) (0.5-3 mg/kg) into anesthetized rats caused a dose-dependent reduction of the transmucosal potential difference (PD) and intraluminal pH (pH), and induced gastric lesions within 2 h. These same changes were seen with an intraperitoneal injection of histamine, but not with serotonin. There was a significant correlation between the lesion index and the PD reduction, although the integrity of the resting gastric mucosal barrier remained unaltered. The PD reduction caused by 48/80 was dose-dependently inhibited by tripelennamine (H1-antagonist) and FPL-52694 (mast cell stabilizer) and partially suppressed by methysergide (serotonin antagonist), but the changes in pH were prevented by FPL-52694 and cimetidine (H2-antagonist). The reduction of PD and pH induced by histamine was inhibited by tripelennamine or cimetidine, respectively, but these responses were not inhibited by FPL-52694 or methysergide. Gastric lesions induced by 48/80 were potently inhibited by tripelennamine and FPL-52694, and partially by cimetidine, whereas those induced by histamine were significantly prevented by tripelennamine and cimetidine, but not by FPL-52694. Methysergide had no effect on the development of gastric lesions in response to 48/80 or histamine. These results suggest that a single injection of 48/80 reduced the PD and stimulated acid secretion, thereby producing gastric lesions. These effects of 48/80 may be due to activation of H1- and H2-receptors by acutely released endogenous histamine.
Insights
Compound 48/80 causes gastric lesions by reducing potential difference and pH, likely through histamine release. Antihistamines and mast cell stabilizers protect against these effects in rats.
Area of Science:
- Gastroenterology
- Pharmacology
- Physiology
Background:
- Compound 48/80 is known to induce mast cell degranulation.
- Histamine release is implicated in various physiological and pathological processes, including gastric function.
Purpose of the Study:
- To investigate the effects of compound 48/80 on gastric mucosal integrity and function in rats.
- To elucidate the mechanisms underlying compound 48/80-induced gastric changes, particularly the role of histamine.
Main Methods:
- Rats were administered intraperitoneal injections of compound 48/80, histamine, or serotonin.
- Transmucosal potential difference (PD), intraluminal pH, and gastric lesions were measured.
- The effects of various antagonists (H1, H2, serotonin) and a mast cell stabilizer were assessed.
Main Results:
- Compound 48/80 induced a dose-dependent reduction in PD and pH, and caused gastric lesions.
- Histamine administration produced similar changes, while serotonin did not.
- PD reduction by 48/80 was inhibited by H1-antagonists and mast cell stabilizers.
- Gastric lesions induced by 48/80 were inhibited by H1-antagonists, mast cell stabilizers, and partially by H2-antagonists.
Conclusions:
- Compound 48/80 triggers gastric mucosal changes and lesions through the release of endogenous histamine, acting on both H1 and H2 receptors.
- Mast cell stabilization and H1 receptor blockade are effective in preventing compound 48/80-induced gastric damage.