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Somatostatin prevents cysteamine-induced duodenal ulcer
European Journal of Pharmacology, 44 (1977) 195--196
195
© Elsevier/North-Holland Biomedical Press
Rapid communication SOMATOSTATIN PREVENTS CYSTEAMINE-INDUCED DUODENAL ULCER
ULRICH SCHWEDES, KLAUS USADEL and SANDOR SZABO* Zentrum der Inneren Medizin, Abteilung fur Endokrinologie, Johann Wolfgang Goethe Universit~t, Frankfurt/ Main, Fed. Rep. Germany, and *Departments of Pathology, Peter Bent Brigham Hospital, Harvard Medical School, Boston, Massachusetts 02115, U.S.A.
Received 24 May 1977, accepted 26 May 1977
A simple model of acute and chronic duodenal ulcer disease in rats has been recently introduced (Selye and Szabo, 1973; Szabo et al., 1976). Ulcer formation is associated with increased gastric acid output, elevated serum gastrin and delayed gastric emptying (Szabo et al., 1977). Somatostatin (somatotropin-releasing inhibiting factor) originally isolated from the hypothalamus was shown to inhibit the secretion of immunoreactive growth or somatotropic h o r m o n e (STH) (Guillemin and Gerich, 1976). Recently, immunoreactive somatostatin producing cells have been identified also in the stomach, d u o d e n u m and pancreatic D-cells (Guillemin and Gerich, 1976). We, therefore, investigated the possible role of somatostatin in duodenal ulcerogenesis. Female Sprague-Dawley (200--250 g) rats were divided into 6 groups (table 1) and maintained on Purina Lab Chow and tap water ad libitum. Groups 1 and 2 were given 28 mg/100g of cysteamine--HC1 (Aldrich) as 10% aqueous solution, p.o. by rubber stomach tube, three times within 8 h (beginning at 9 A.M.). Under similar conditions, Groups 3 and 4 received 25 mg/100 g, while Groups 5 and 6 were administered 22 mg/ 100 g cysteamine. Groups 1, 3 and 5 served *Correspondence should be addressed to Dr. S. Szabo.
as controls while rats of Groups 2, 4 and 6 were injected 5 times, during an interval of 12 h, starting at 8 P.M. on the day before cysteamine, with 250 pg synthetic linear somatostatin as a protamine zinc suspension. This suspension consisted of 250 ~g somatostatin and 1 mg protamine sulfate in 1 ml double-distilled water + 0.26 mg zinc chloride in 1 ml double-distilled water (Serono, Pharmazeutische Pr~iparate, Freiburg, W. Germany). Survivors were sacrificed 48 h after the initial administration of cysteamine. The intensity of ulcers was rated on a scale where 0 = no ulcer, 1 = mucosal erosion, 2 = deep ulcer with transmural necrosis, 3 = perforated and/ or penetrated ulcer. The statistical significance of the intensity of duodenal ulcer was calculated by Student's t-test. The ulcer incidence and mortality rates were arranged in a 2 X 2 contingency table and their statistical significance was computed by the 'exact probability test' of Fisher and Yates. Tissue samples were fixed in 10% formaldehyde for histologic examination. Results presented in table 1 show that under our experimental conditions, 28 mg/ 100 g of cysteamine caused 90% mortality, and most of the rats died before development of advanced duodenal ulcer. Nevertheless, somatostatin significantly decreased
196 TABLE 1 Effect of Somatostatin on Cysteamine-induced Duodenal Ulcer. Group
Treatment
Duodenal ulcer
Cysteamine
Somatostatin
Intensity (scale: 0--3)
Incidence (positive/total)
Mortality (dead/total)
1 2
28 mg 28 mg
no yes
1.1 -+ 0.3 0.4 + 0.1"
7/10 5/12
9/10 5/12"
3 4
25 mg 25 mg
no yes
2.8 -+ 0.2 0.0 -+ 0"*
5/5
3/5
0/5"
0/5
5 6
22 mg 22 mg
no yes
1.6 + 0.6 0.0 -+ 0*
4/5 0/5
2/5 1/5
*p<0.05. **p<0.005.
the mortality, the intensity of duodenal ulcer and adrenocortical necrosis produced by the high dose of cysteamine. The intermediate dose (25 mg/100 g) of cysteamine caused 100% incidence of advanced duodenal ulcer. The most severe ulcer was (as in man) on the antimesenteric, anterior wall of the duodenum, and a second ('kissing') ulcer usually penetrated into the pancreas. Treatment with somatostatin completely prevented the duodenal ulcer formation, and abolished the mortality induced by cysteamine. Similar beneficial effects of somatostatin were observed in animals given low (22 mg/100 g) doses of cysteamine. The mechanism for the protective effect of somatostatin against experimental duodenal ulcer is not clear. Cysteamine markedly increased basal gastrin levels in rats and enhanced the gastrin response to food and peptone (Lichtenberger et al., submitted). Somatostatin decreased both basal gastrin and the chemically elevated gastrin levels in the serum of several species in vivo and in vitro (Guillemin and Gerich, 1976). The gastric secretory response to histamine and pentagastrin was counteracted by somatostatin (Guillemin and Gerich, 1976). Although elevated serum gastrin level does not solely account for the duodenal ulcer produced by cysteamine, our studies suggest
that interaction of somatostatin and gastrin secretion or a direct inhibition of gastric acid output by somatostatin in cysteamine treated rats might be involved in this beneficial effect of somatostatin. In a patient with bleeding duodenal ulcer, somatostatin infusion apparently stopped the bleeding (Mattes et al., 1975). Thus, besides potential applications in other diseases (Guillemin and Gerich, 1976), somatostatin might help elucidate the pathogenesis of duodenal ulcer and possibly be of some therapeutic value. References Selye, H. and S. Szabo, 1973, An experimental model for the production of perforating duodenal ulcers by cysteamine in the rat, Nature 244,458. Szabo, S., L.R. Haith Jr., and E.S. Reynolds, 1976, Chemical induction of chronic duodenal ulcer' in the rat, Amer. J. Path. 82, 40a. Szabo, S., E.S. Reynolds, L.M. Lichtenberger, L.R. Haith, Jr., and V.J. Dzau, 1977, Pathogenesis of duodenal ulcer. Gastric hyperactivity caused by propionitrile and cysteamine in rats, Res. Commun. Chem. Path. Pharmacol. 16,311. Guillemin, R. and J.E. Gerich, 1976, Somatostatin: physiological and clinical significance, Ann. Rev. Med. 2 7 , 3 7 9 . Mattes, P., S. Raptis, T. Heil, H. Rasche, and R. Scheck, 1975, Extended somatostatin treatment of a patient with bleeding ulcer, Horm. Metab. Res., 7 , 5 0 8 .
195
© Elsevier/North-Holland Biomedical Press
Rapid communication SOMATOSTATIN PREVENTS CYSTEAMINE-INDUCED DUODENAL ULCER
ULRICH SCHWEDES, KLAUS USADEL and SANDOR SZABO* Zentrum der Inneren Medizin, Abteilung fur Endokrinologie, Johann Wolfgang Goethe Universit~t, Frankfurt/ Main, Fed. Rep. Germany, and *Departments of Pathology, Peter Bent Brigham Hospital, Harvard Medical School, Boston, Massachusetts 02115, U.S.A.
Received 24 May 1977, accepted 26 May 1977
A simple model of acute and chronic duodenal ulcer disease in rats has been recently introduced (Selye and Szabo, 1973; Szabo et al., 1976). Ulcer formation is associated with increased gastric acid output, elevated serum gastrin and delayed gastric emptying (Szabo et al., 1977). Somatostatin (somatotropin-releasing inhibiting factor) originally isolated from the hypothalamus was shown to inhibit the secretion of immunoreactive growth or somatotropic h o r m o n e (STH) (Guillemin and Gerich, 1976). Recently, immunoreactive somatostatin producing cells have been identified also in the stomach, d u o d e n u m and pancreatic D-cells (Guillemin and Gerich, 1976). We, therefore, investigated the possible role of somatostatin in duodenal ulcerogenesis. Female Sprague-Dawley (200--250 g) rats were divided into 6 groups (table 1) and maintained on Purina Lab Chow and tap water ad libitum. Groups 1 and 2 were given 28 mg/100g of cysteamine--HC1 (Aldrich) as 10% aqueous solution, p.o. by rubber stomach tube, three times within 8 h (beginning at 9 A.M.). Under similar conditions, Groups 3 and 4 received 25 mg/100 g, while Groups 5 and 6 were administered 22 mg/ 100 g cysteamine. Groups 1, 3 and 5 served *Correspondence should be addressed to Dr. S. Szabo.
as controls while rats of Groups 2, 4 and 6 were injected 5 times, during an interval of 12 h, starting at 8 P.M. on the day before cysteamine, with 250 pg synthetic linear somatostatin as a protamine zinc suspension. This suspension consisted of 250 ~g somatostatin and 1 mg protamine sulfate in 1 ml double-distilled water + 0.26 mg zinc chloride in 1 ml double-distilled water (Serono, Pharmazeutische Pr~iparate, Freiburg, W. Germany). Survivors were sacrificed 48 h after the initial administration of cysteamine. The intensity of ulcers was rated on a scale where 0 = no ulcer, 1 = mucosal erosion, 2 = deep ulcer with transmural necrosis, 3 = perforated and/ or penetrated ulcer. The statistical significance of the intensity of duodenal ulcer was calculated by Student's t-test. The ulcer incidence and mortality rates were arranged in a 2 X 2 contingency table and their statistical significance was computed by the 'exact probability test' of Fisher and Yates. Tissue samples were fixed in 10% formaldehyde for histologic examination. Results presented in table 1 show that under our experimental conditions, 28 mg/ 100 g of cysteamine caused 90% mortality, and most of the rats died before development of advanced duodenal ulcer. Nevertheless, somatostatin significantly decreased
196 TABLE 1 Effect of Somatostatin on Cysteamine-induced Duodenal Ulcer. Group
Treatment
Duodenal ulcer
Cysteamine
Somatostatin
Intensity (scale: 0--3)
Incidence (positive/total)
Mortality (dead/total)
1 2
28 mg 28 mg
no yes
1.1 -+ 0.3 0.4 + 0.1"
7/10 5/12
9/10 5/12"
3 4
25 mg 25 mg
no yes
2.8 -+ 0.2 0.0 -+ 0"*
5/5
3/5
0/5"
0/5
5 6
22 mg 22 mg
no yes
1.6 + 0.6 0.0 -+ 0*
4/5 0/5
2/5 1/5
*p<0.05. **p<0.005.
the mortality, the intensity of duodenal ulcer and adrenocortical necrosis produced by the high dose of cysteamine. The intermediate dose (25 mg/100 g) of cysteamine caused 100% incidence of advanced duodenal ulcer. The most severe ulcer was (as in man) on the antimesenteric, anterior wall of the duodenum, and a second ('kissing') ulcer usually penetrated into the pancreas. Treatment with somatostatin completely prevented the duodenal ulcer formation, and abolished the mortality induced by cysteamine. Similar beneficial effects of somatostatin were observed in animals given low (22 mg/100 g) doses of cysteamine. The mechanism for the protective effect of somatostatin against experimental duodenal ulcer is not clear. Cysteamine markedly increased basal gastrin levels in rats and enhanced the gastrin response to food and peptone (Lichtenberger et al., submitted). Somatostatin decreased both basal gastrin and the chemically elevated gastrin levels in the serum of several species in vivo and in vitro (Guillemin and Gerich, 1976). The gastric secretory response to histamine and pentagastrin was counteracted by somatostatin (Guillemin and Gerich, 1976). Although elevated serum gastrin level does not solely account for the duodenal ulcer produced by cysteamine, our studies suggest
that interaction of somatostatin and gastrin secretion or a direct inhibition of gastric acid output by somatostatin in cysteamine treated rats might be involved in this beneficial effect of somatostatin. In a patient with bleeding duodenal ulcer, somatostatin infusion apparently stopped the bleeding (Mattes et al., 1975). Thus, besides potential applications in other diseases (Guillemin and Gerich, 1976), somatostatin might help elucidate the pathogenesis of duodenal ulcer and possibly be of some therapeutic value. References Selye, H. and S. Szabo, 1973, An experimental model for the production of perforating duodenal ulcers by cysteamine in the rat, Nature 244,458. Szabo, S., L.R. Haith Jr., and E.S. Reynolds, 1976, Chemical induction of chronic duodenal ulcer' in the rat, Amer. J. Path. 82, 40a. Szabo, S., E.S. Reynolds, L.M. Lichtenberger, L.R. Haith, Jr., and V.J. Dzau, 1977, Pathogenesis of duodenal ulcer. Gastric hyperactivity caused by propionitrile and cysteamine in rats, Res. Commun. Chem. Path. Pharmacol. 16,311. Guillemin, R. and J.E. Gerich, 1976, Somatostatin: physiological and clinical significance, Ann. Rev. Med. 2 7 , 3 7 9 . Mattes, P., S. Raptis, T. Heil, H. Rasche, and R. Scheck, 1975, Extended somatostatin treatment of a patient with bleeding ulcer, Horm. Metab. Res., 7 , 5 0 8 .