PubMed · 5735451
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J J Barcia-Goyanes, J L Barcia-Salorio. 1968. Pallencephalography.. https://doi.org/10.1016/s0079-6123(08)61462-4
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Mercaptomethylimidazole (2-Mercapto-1-methylimidazole, MMI), an antithyroid drug of thionamide group, significantly activated the parietal cell for acid secretion, as evidenced by increased O2 consumption by more than 2.5-fold over the basal level. When compared, MMI-induced activation was similar to that of histamine but significantly higher than that of isobutylmethylxanthine or carbachol. Activation by MMI was not prevented by receptor blockers of the parietal cell, indicating that its effect was not mediated through the cell surface histamine-H2 receptor or the muscarinic receptor. However, the activation was almost completely blocked only by omeprazole, an established inhibitor of the terminal proton-pumping H+-K+-ATPase of the parietal cell. That MMI-induced activation was coupled with the H+ transport was further confirmed by significant increase in [14C]-aminopyrine uptake by MMI in rabbit gastric gland preparation. MMI-dependent activation of the parietal cell correlated well with the inhibition of the endogenous peroxidase activity. In vitro studies indicated that MMI irreversibly inactivated both peroxidase and catalase activity of the parietal cell in presence of H2O2. As inactivation of these H2O2-scavenging enzymes should increase accumulation of intracellular H2O2, the effect of latter was studied on acid secretion. H2O2 at a low concentration, stimulated acid secretion by sevenfold in isolated gastric mucosa, which was sensitive to omeprazole. It also significantly stimulated [14C]-aminopyrine uptake in gastric gland preparation. We suggest that MMI activated parietal cells to stimulate acid secretion by endogenous accumulation of H2O2 through inactivation of the peroxidase-catalase system.
A new series of N-Substituted 2-(benzhydryl- and benzylsulfinyl)nicotinamides 7 and 8 were synthesized. Upon acid activation in the acidic environment of the parietal cell, these compounds are converted into their active forms, 2,3-dihydro-3-oxoisothiazolo[5,4-b]pyridines 5, which inhibit gastric H+/K(+)-ATPase. Inhibitory activities against [14C]aminopyrine accumulation stimulated by dibutyryl cAMP in isolated rabbit parietal cells in vitro and histamine-induced gastric acid secretion in pylorus-ligated rats by intraduodenal administration in vivo were evaluated, and the structure-activity relationships were examined. Among the compounds synthesized, 2-[(2,4-dimethoxybenzyl)sulfinyl]-N-(4-pyridyl)nicotinamide (8b) showed potent inhibitory activities in vitro and in vivo equivalent to those of omeprazole, a typical H+/K(+)-ATPase inhibitor. Moreover, 8b was much more stable at neutral and weakly acidic pH than omeprazole, lansoprazole, and pantoprazole. Compound 8b is considered to be a promising agent for treating acid-related gastrointestinal disorders.
BACKGROUND: Liver cell proliferation after partial hepatectomy in rats has been thoroughly investigated. Although DNA synthesis and morphologic restoration have been studied in this rat model, the functional capacity of the remnant liver during regeneration has not been elucidated. METHODS: We measured the indocyanine green disappearance rate (ICG-k) and serum aminopyrine (CLamp) in rats at various intervals after two-thirds hepatectomy. Morphologic restoration of the liver after hepatectomy was evaluated on the basis of remnant liver weight, proliferating cell nuclear antigen labeling index, and the DNA content of the regenerating liver. Serial changes in ICG-k and CLamp after two-thirds hepatectomy were compared with the degree of morphologic restoration. RESULTS: ICG-k and CLamp were reduced by one third in rats after two-thirds hepatectomy. Although the rate of restoration of remnant liver weight was steady after hepatectomy, ICG-k and CLamp were lowest about 36 hours after hepatectomy. The restoration of ICG-k was comparable to that of liver weight, but the restoration of CLamp was delayed. CONCLUSIONS: Functional liver capacity was minimal during parenchymal cell mitosis in the regenerating liver. Functional restoration after two-thirds hepatectomy was delayed in comparison with morphologic restoration in rat.