New model of cytoprotection adaptive cytoprotection in rats: endogenous small irritants, antiulcer agents and indomethacin

Adaptive cytoprotection in the stomach was originally defined by applying t he exogenous irritants only. The contribution of endogenous irritants as in ductors of initial lesions was not specially evaluated. No attempt was made to either focus antiulcer agent activity on adaptive cytoprotection, or sp lit their 'cytoprotection' into complex adaptive cytoprotective activity an d simple cytoprotective effects. Agents had so far not been applied simulta neously with the second challenge with ethanol (or irritant), when differen ces between cytoprotection and adaptive cytoprotection appear. Gastrojejuna l anastomosis for 24 h in rats was introduced as new model for analyzing cy toprotection/adaptive cytoprotection. The contribution of the up-normal lev el of endogenous irritants and the endogenous small irritant-induced minor lesions during the adaptive cytoprotection were studied. The effect of late challenge with 96% ethanol in the presence of an up-normal level of endoge nous irritants and endogenous small irritant-induced minor lesions was comp ared with results of classic studies of ethanol-induced gastric lesions in normal rats (1 ml/rat i.g.). Antiulcer agents or a prostaglandins-synthesis inhibitor, indomethacin, given once only in classic studies, were given at several points during injury induction: (i) surgery, (ii) mild ethanol, (i ii) strong ethanol, (iv) strong ethanol applied after a suitable period fol lowing either mild ethanol or surgery). Their effects were compared in rats treated as follows: exogenous irritant studies (96% or 20% ethanol), exoge nous/exogenous irritant studies (20% ethanol 1 h before 96% ethanol), endog enous irritant studies (gastrojejunal anastomosis for 24 h), and endogenous /exogenous irritant studies (gastrojejunal anastomosis for 24 h before 96% ethanol). Characteristic of the various irritants differed: the (preceding) small irritants (exogenous (i.e., mild ethanol in healthy intact rats) (ex ogenous irritant studies) vs, endogenous (e.g., (increased) gastric acid se cretion, duodenal reflux in gastric content in rats with termino-lateral ga strojejunal anastomosis) (endogenous irritant studies)). These factors caus ed modifications of agents' activities not, as initially thought, giving si mple 'cytoprotection', but being only cytoprotective, or adaptive cytoprote ctive, or both cytoprotective and adaptive cytoprotective. Atropine (10 mg/ kg i.p.) and ranitidine (10 mg) had only cytoprotective activity (exogenous irritant-studies), whereas pentadecapeptide BPC157 (10 mu g or 10 ng), and omeprazole (10 mg) had mainly adaptive cytoprotective activity (endogenous /exogenous irritant studies) or both cytoprotective and adaptive cytoprotec tive activities (exogenous/exogenous irritant studies). Augmentation of the lesions by indomethacin (5 mg/kg s.c.), showed that only events preceding the late challenge with ethanol may be prostaglandin-dependent in both mode ls. The second, adaptive cytoprotective part, seen after late ethanol chall enge, may be either prostaglandin-dependent (exogenous/exogenous irritant s tudies) or non-dependent (endogenous/exogenous irritant studies). Both spon taneous lesion reduction, as an essential mechanism of adaptive cytoprotect ion, and the further lesion reduction by agents, such as pentadecapeptide B PC 157 and omeprazole, suggests that these agents function as an essential link between the various reactions in cytoprotection/adaptive cytoprotectio n. (C) 1999 Elsevier Science B.V. All rights reserved.