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Octreotide Inhibits the Enterochromaffin-Like Cell but Not

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Octreotide Inhibits the Enterochromaffin-Like Cell but Not 109 Octreotide inhibits the enterochromaffin-like cell but not peroxisome proliferator-induced hypergastrinemia I Bakke, A K Sandvik and H L Waldum Department of Physiology and Biomedical Engineering, Norwegian University of Science and Technology, and Department of Medicine, University Hospital of Trondheim, Trondheim, Norway (Requests for offprints should be addressed to I Bakke, Department of Physiology and Biomedical Engineering, Faculty of Medicine, Norwegian University of Science and Technology, N-7489 Trondheim, Norway; Email: [email protected]) ABSTRACT The peroxisome proliferator ciprofibrate induces hypergastrinemia (P<0·001). These rats had pro- hypergastrinemia and as a consequence, found ECL cell hyperplasia, confirmed by an enterochromaffin-like (ECL) cell hyperplasia. The increase in chromogranin A (CgA) and histidine mechanism for the gastrin cell stimulation is decarboxylase (HDC) mRNA, density of neuro- unknown. The somatostatin analog octreotide LAR endocrine and ECL cells and plasma histamine (long-acting release) was used to see if the levels (all P<0·001). Octreotide LAR did not affect stimulating effects of ciprofibrate could be attenu- ciprofibrate stimulation of gastrin cells, but all ated. Female Fischer rats were dosed with cipro- parameters of ECL cell hyperplasia were reduced fibrate (50 mg/kg body weight per day) alone or (P<0·001). Octreotide LAR also significantly combined with octreotide LAR (10 mg/30 days) for inhibited basal ECL cell function and growth. 60 days. Plasma gastrin and histamine, gastric Ciprofibrate stimulates gastrin cell activity by a endocrine cell densities and mRNA abundances mechanism unaffected by octreotide, but octreotide were measured. Ciprofibrate increased gastrin does inhibit basal and gastrin-stimulated ECL cell mRNA abundance (P<0·05), gastrin cell number function and growth. (P<0·001) and cell area (P<0·01), and induced Journal of Molecular Endocrinology (2000) 25, 109–119 INTRODUCTION blockers (Ryberg et al. 1989). However, in recent studies, we have shown that ciprofibrate induces The peroxisome proliferator group of substances hypergastrinemia without reducing gastric acidity, have a tumorigenic effect on the liver, inducing and that high doses even decrease gastric pH, hyperplasia and hepatocellular carcinomas probably because of the increased stimulatory effect (Issemann & Green 1990). The exact mechanism of circulating gastrin (Martinsen et al. 1996). We for the neoplastic effect is not known, but it is have also shown that the hypergastrinemic effect of non-genotoxic (O’Brien et al. 1996). Some of these ciprofibrate begins later (14 days) than the effect of substances, like ciprofibrate and other fibrates gastric acid inhibitors (Ryberg et al. 1989) and that (phenoxyisobutyrate derivatives), also induce co-administration with omeprazole potentiates the hypergastrinemia under sustained exposure (Eason hypergastrinemic effect (Hammer et al. 1998). et al. 1988c, Spencer et al. 1989). Gastrin stimulates Thus, ciprofibrate causes hypergastrinemia through function of the enterochromaffin-like (ECL) cell a mechanism independent of gastric pH. Cipro- and long-term hypergastrinemia causes ECL cell fibrate not only increases gastrin mRNA abundance hyperplasia and carcinoids (Ryberg et al. 1989). and raises serum gastrin concentration, but also The mechanism for the stimulating effect of tends to increase expression of somatostatin in the fibrates on the gastrin-producing G cell is also antrum (Hammer et al. 1998, Waldum et al. 1998). unknown. Previously, it was claimed that the This is different from the reciprocal relationship hypergastrinemia was secondary to reduced gastric that normally exists between gastrin and somato- acidity (Eason et al. 1988a,b), similar to treatment statin in the antrum (Lundell et al. 1988, Wu et al. with proton pump inhibitors and histamine H2 1991). Similar dual increase of these antral peptides Journal of Molecular Endocrinology (2000) 25, 109–119 Online version via http://www.endocrinology.org 0952–5041/00/025–109 2000 Society for Endocrinology Printed in Great Britain Downloaded from Bioscientifica.com at 10/02/2021 12:19:38PM via free access 110 and others · Effects of ciprofibrate and octreotide on gastric endocrine cells is also seen after stimulation with gastrin-releasing MA3–923; Affinity BioReagents, Inc., Golden, CO, polypeptide and administration of glucocorticoids USA). Histamine RIA kits were purchased from (Holst et al. 1987, Xynos et al. 1987, Sandvik et al. Immunotech (Marseilles, France), 32P-labeled nucleo- 1989, Okazaki et al. 1993). tides from Amersham International (Amersham, Somatostatin is widely distributed in the body, Bucks, UK), nylon membranes from Boehringer suppressing biological events like hormone release Mannheim (Mannheim, Germany) and NICK and cell proliferation (Lamberts et al. 1991). In the columns from Pharmacia Biotech AB (Uppsala, stomach, D cells are located in proximity to their Sweden). target cells, and exert a restraint on the secretion of histamine and gastrin (Saffouri et al. 1980, Sandvik & Waldum 1988, Karnik et al. 1989). Receptors Study design for somatostatin are found on ECL and G cells The study was approved by the animal welfare (Borin et al. 1996, Zaki et al. 1996). Long-acting committee of the University Hospital of somatostatin analogs have been developed for Trondheim. Female Fischer rats (200–250 g) were therapeutic use and are especially useful in patients assigned to four groups (I–IV) of 12, 14, 12 and 12 with secretory neuroendocrine tumors (Lamberts rats respectively, and housed in wire-bottom cages et al. 1991). Octreotide is effective in controlling at 20 C with a relative humidity of 40–45%, a 12 h hypergastrinemia and in inhibiting both fundic light:12 h darkness cycle and free access to endocrine preneoplastic growth and tumor growth commercial rat chow and water. All groups were in the stomach (Modlin et al. 1992, Bordi et al. given 1 ml tap water with or without ciprofibrate 1993, D’Adda et al. 1996). (50 mg/kg body weight) once daily by gastric The aim of this study was to further assess the so intubation. Octreotide LAR or placebo drug far unknown and maybe novel mechanism for the (10 mg) was dissolved in 1 ml of the supplied effect of ciprofibrate on the endocrine cells in the rat vehicle, and 0·5 ml was injected i.m. in both thighs stomach, by looking at both changes in morphology on day 1 and day 28 of the study period. Group I of the antral and oxyntic mucosa and the mRNA (control) was given tap water and placebo drug, expression of secretory products. Furthermore, we group II ciprofibrate and placebo drug, group III wanted to see if the somatostatin analog octreotide tap water and octreotide LAR and group IV both LAR (long-acting release) could attenuate these ciprofibrate and octreotide LAR. The purpose of effects of ciprofibrate. this study was to examine the mechanisms of both ciprofibrate and octreotide action on endocrine cells in antral and oxyntic mucosa. Therefore, the doses MATERIALS AND METHODS used were not clinically matched, but instead set very high to ensure maximal effects of the drugs. Materials The depot formulation of octreotide, octreotide The drugs used were ciprofibrate (2-[4(6–2,2 LAR, was used because of its convenience in dichlorocyclopropyl)phenoloxyl]-2-methyl propa- long-term studies, reducing the number of injec- noic acid) (Modalim; Sanofi-Synthelabo, Alnwick, tions and giving a more stable plasma level of the Northumberland, UK) and octreotide LAR, a somatostatin analog during the study period. generous gift from Novartis Pharma AG (Basel, Initially the rats were given 80 mg/kg ciprofibrate, Switzerland). Fischer rats were purchased from but because of weight loss in some of the rats after Møllegaard’s Breeding Center (Skensved, 1 week, the dose was reduced to 50 mg/kg. One rat Denmark). Immunohistochemistry was done with in group II died after 2 weeks. After injection of the avidin-biotin-complex (ABC) technique, using a octreotide LAR/placebo on day 28, further weight Vectastain peroxidase-rabbit-ABC-kit (PK-4001) loss in some rats made it necessary to stop the and a peroxidase substrate-kit (AEC SK4200) from administration of drug to these rats for 6–12 days. Vector Laboratories, Inc. (Burlingame, CA, USA). The rats were weighed at the start and weekly Antisera used were: rabbit polyclonal anti-histidine throughout the study. Blood was taken from the decarboxylase (HDC) (cat. no. B260–1; Euro- femoral vein of anesthetized (0·3 ml/100 g body diagnostics, Malmö, Sweden), rabbit polyclonal weight of 2·5 mg/ml fluanison, 0·05 mg/ml fentanyl anti-chromogranin A (CgA) (cat. no. 20086; and 1·25 mg/ml midazolam) rats on day 1, day 21 INCSTAR, Stillwater, MN, USA), rabbit poly- and day 60. Plasma was frozen for later determi- clonal anti-human somatostatin (cat. no. A566) and nation of histamine and gastrin by RIA (Kleveland rabbit polyclonal anti-human gastrin (cat. no. A568) et al. 1985, Waldum et al. 1989). At the end of both from DAKO A/S (Glostrup, Denmark) and the study, the rats were anesthetized and killed mouse monoclonal anti--H+/K+ATPase (cat. no by decapitation. The stomachs were immediately Journal of Molecular Endocrinology (2000) 25, 109–119 www.endocrinology.org Downloaded from Bioscientifica.com at 10/02/2021 12:19:38PM via free access Effects of ciprofibrate and octreotide on gastric endocrine cells · and others 111 removed, opened at the major curvature and rinsed Plasmids were linearized, and antisense RNA in saline. Biopsies were taken from the oxyntic and probes labeled with 32P by transcription according antral mucosa and fixed in 4% buffered formalde- to standard protocols and purified on NICK hyde or homogenized for RNA extraction. The columns. homogenates were immediately frozen at 80 C. Total RNA (20 µg/well) was electrophoresed in 1% agarose-formaldehyde gels, electroblotted onto nylon membranes and crosslinked by UV Immunohistochemical procedures irradiation. Membranes were prehybridized for 4 h Fixed tissue specimens were dehydrated, embedded at 65 Cin5saline-sodium phosphate EDTA in paraffin and cut perpendicular to the mucosal (SSPE) buffer (1SSPE is 0·18 M NaCl, 10 mM surface in 5 µm thick sections.
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