Mechanisms of irritative activity of compound 48/80 on rat gastric mucosa.
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.
D000818:Animals; D002867:Chromones / Q000494:pharmacology; D002927:Cimetidine / Q000494:pharmacology; D004553:Electric Conductivity; D005753:Gastric Mucosa / Q000187:drug effects* / Q000502:physiology; D006632:Histamine / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008784:Methysergide / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000494:pharmacology; D014309:Tripelennamine / Q000494:pharmacology; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology*
D002867:Chromones; D012701:Serotonin; D014309:Tripelennamine; D003189:p-Methoxy-N-methylphenethylamine; C029061:FPL-52694; D002927:Cimetidine; D006632:Histamine; D008784:Methysergide