The resistance of guinea‐pigs to cortisone ulcerogenesis

It is generally, though not universally, accepted that the prolonged treatment of man and experimental animals with high doses of glucocorticoids can induce fresh peptic ulcers, reactivate previously quiescent ulcers or exacerbate latent ulcers (Sandweiss, 1954; Gray, 1961 ; Crean, 1963). We had observed that ulcers did not develop in the stomach of guinea-pigs treated with high doses of cortisone for 10 days, even when animals so treated were also subjected to pylorus ligation at the time of the last cortisone injection (Heisler & Kovacs, 1967a). We have now subjected guinea-pigs to prolonged cortisone treatment alone or with semi-starvation, restraint and acetylsalicyclic acid administration, to observe whether cortisone produced gastric ulceration under any of these conditions. Drugs were cortisone acetate (Cortone; Merck Sharp & Dohme) and acetylsalicyclic acid (Lymans Ltd.). These were always given at 9 a.m. ; control guinea-pigs were treated with the same volume of physiological saline. For restraint, the technique described by Brodie & Hanson (1960) was used. Animals were fasted 24 h before the experiment: water was allowed at all times. Cortisone was injected immediately before restraint. Gastric ulceration was evaluated according to the “all or nothing” method of Bonfils & Lambling (1963). In some experiments fasted animals were subjected to pylorus ligation (Shay, Sun & Gruenstein, 1954) and then restrained. The duration of restraint in unligated guinea-pigs was 24 h and in pylorus-ligated animals 16 h. Animals in both groups were injected with physiological saline (3 ml, s.c.) to prevent dehydration. Gastric acidity was measured by titrating the samples, after centrifugation, with 0.1 N NaOH using Topfer’s reagent and phenolphthalein as indicators. The significance of differences between means was calculated by Student’s r-test and in the “restraint” method the significance was estimated by the x2 test. Prolonged treatment of 10 guinea-pigs with 100 mg/kg of cortisone injected subcutaneously once daily for 14-28 days did not bring about gastric ulceration. The effect on gastric ulceration of cortisone treatment combined with semistarvation was determined in 12 guinea-pigs. Six guinea-pigs were injected once daily for 10 days with cortisone (100 mg/kg, s.c.), 6 animals received the same dose of cortisone by mouth, since according to Gray (1961) cortisone so given possesses a greater ulcerogenic liability than via the subcutaneous route. The guinea-pigs in both groups were fed for only 5 of every 24 h (12-5 p.m.) except on the last day of treatment when they were fasted all day. Animals were killed 24 h after the last injection of cortisone, the stomachs removed and examined macroscopically. The effect of cortisone combined with restraint on gastric ulceration showed that in the control group (23 animals where restraint was for 24 h) 87% of the animals developed gastric ulceration-no particular anatomical distribution was noted. In the cortisonetreated group (14 animals, cortisone 100 mg/kg, S.C. for 3 days, the last dose before 24 h restraint) the incidence of ulceration was 42.9% which is a significant reduction (P < 0.005). Since cortisone stimulates gastric acid secretion in pylorus-ligated guinea-pigs (Heisler & Kovacs, 1967a) we felt that a combination of restraint and pylorus ligation might increase the incidence of ulceration after cortisone administration. This experiment is illustrated in Table 1. Cortisone significantly increased the free and total acid output in comparison with the respective outputs in animals not receiving cortisone. The incidence of ulceration in the latter group was 85% and in the cortisone-treated group 50%. The hyperacidity observed in cortisone-treated guineapigs did not increase the incidence of gastric ulceration, rather, there was a definite Male guinea-pigs, initially 300-340 g, were used.