Central leptin and cholecystokinin in gastroprotection against ethanol-induced damage

被引:41
作者
Brzozowski, T
Konturek, PC
Konturek, SJ
Pierzchalski, P
Bielanski, W
Pajdo, R
Drozdowicz, D
Kwiecien, S
Hahn, EG
机构
[1] Jagiellonian Univ, Sch Med, Dept Physiol, PL-31531 Krakow, Poland
[2] Univ Erlangen Nurnberg, Dept Med 1, Erlangen, Germany
关键词
leptin; cholecystokinin; gastroprotection; nitric oxide; sensory nerves; vagal nerves; gastric blood flow; gastric secretion;
D O I
10.1159/000007805
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background: Leptin, a product of the ob gene controlling food intake, has recently been detected in the stomach and shown to be released by cholecystokinin (CCK) and to induce gastroprotection against various noxious agents, but it is not known whether centrally applied leptin influences gastric secretion and mucosal integrity. Aims: In this study we compared the effects of leptin and CCK-8 applied intracerebroventricularly (i.c.v.) on gastric secretion and gastric mucosal lesions induced by topical application of 75% ethanol. Methods: Several major series of Wistar rats were used in this study. The effects of leptin or CCK applied i.c.v. on gastric secretion were examined using conscious rats with gastric fistulas. For the studies on gastroprotection the following series of rats were used to determine the effects of: (A) leptin and CCK applied centrally on this protection and the blockade of CCKA with loxiglumide (30 mg/kg i.p.) and CCKB receptors with RPR 102681 (30 mg/kg i.p.); (B) cutting of vagal nerves; (C) inactivation of sensory nerves by capsaicin (125 mg/kg s.c.); (D) inhibition of calcitonin gene-related peptide (CGRP) receptors with CGRP(8-37) (100 mu g/kg i.p), and (E) suppression of nitric oxide synthase (NOS) with N-G-nitro-L-arginine methyl ester (L-NAME) (5 mg/kg i.v.) on ethanol-induced gastric lesions in rats with or without the i.c.v. pretreatment with leptin or CCK-8. Rats were anesthetized 1 h after ethanol administration to measure the gastric blood flow (GBF) and then to determine the area of gastric lesions by planimetry. Blood was withdrawn for the measurement of plasma leptin and gastrin levels by radioimmunoassay and gastric biopsy samples were collected for the determination of cNOS and iNOS mRNA by RT-PCR. Results: Leptin and CCK-8 (0.01-5 mu g/kg i.c.v.) dose dependently attenuated gastric lesions induced by 75% ethanol; the doses reducing these lesions by 50% (ED50) were 0.8 and 1.2 mu g/kg, respectively. The protective effects of leptin and CCK-8 applied i.c.v. were accompanied by a significant rise in plasma leptin level and an increase in GBF. Blockade of CCKA receptors with loxiglumide abolished the protective and hyperemic effects of CCK but not those of leptin, while RPR 10268, a specific antagonist of CCKB receptors, counteracted leptin-induced protection and the rise in the GBF but failed to influence those afforded by CCK-8. For comparison, pretreatment with peripheral CCK-8 or leptin (10 mu g/kg i.p.) causing a similar rise in the plasma leptin level also significantly reduced gastric lesions induced by 75% ethanol. The protective and hyperemic effects of centrally administered leptin were abolished by vagotomy, producing a fall in plasma leptin levels, and significantly attenuated by sensory denervation with capsaicin, by pretreatment with the CORP antagonist, CGRP(8-37), Or with L-NAME. A strong signal for iNOS mRNA was recorded in the gastric mucosa of leptin- and CCK-8-treated animals, whereas cNOS mRNA was unaffected. Conclusions: (1) Central leptin exerts a potent gastroprotective action at a dose that has no influence on gastric secretion; (2) this protection depends upon CCKB receptors, vagal activity and sensory nerves, and involves hyperemia probably mediated by NO, and (3) leptin mimics the gastroprotective effect of CCK and may be implicated in the protective and hyperemic actions of this peptide on the rat stomach. Copyright (C) 2000 S. Karger AG. Basel.
引用
收藏
页码:126 / 142
页数:17
相关论文
共 56 条
[1]   Physiological role of cholecystokinin B/gastrin receptor in leptin secretion [J].
Attoub, S ;
Levasseur, S ;
Buyse, M ;
Goïot, H ;
Laigneau, JP ;
Moizo, L ;
Hervatin, F ;
Le Marchand-Brustel, Y ;
Lewin, JMM ;
Bado, A .
ENDOCRINOLOGY, 1999, 140 (10) :4406-4410
[2]   The stomach is a source of leptin [J].
Bado, A ;
Levasseur, S ;
Attoub, S ;
Kermorgant, S ;
Laigneau, JP ;
Bortoluzzi, MN ;
Moizo, L ;
Lehy, T ;
Guerre-Millo, M ;
Le Marchand-Brustel, Y ;
Lewin, MJM .
NATURE, 1998, 394 (6695) :790-793
[3]   Leptin enters the brain by a saturable system independent of insulin [J].
Banks, WA ;
Kastin, AJ ;
Huang, WT ;
Jaspan, JB ;
Maness, LM .
PEPTIDES, 1996, 17 (02) :305-311
[4]   Elevated plasma leptin concentrations in early stages of experimental intestinal inflammation in rats [J].
Barbier, M ;
Cherbut, C ;
Aubé, AC ;
Blottière, HM ;
Galmiche, JP .
GUT, 1998, 43 (06) :783-790
[5]   Synergistic interaction between leptin and cholecystokinin to reduce short-term food intake in lean mice [J].
Barrachina, MD ;
Martinez, V ;
Wang, LX ;
Wei, JY ;
Tache, Y .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (19) :10455-10460
[6]  
Bastaki SMA, 1995, EUR J GASTROEN HEPAT, V7, P1199
[7]  
Bohme G. A., 1997, Society for Neuroscience Abstracts, V23, P2409
[8]   Role of beta-adrenoceptors in gastric mucosal integrity and gastroprotection induced by epidermal growth factor [J].
Brzozowski, T ;
Konturek, SJ ;
Sliwowski, Z ;
Pajdo, R ;
Drozdowicz, D ;
Stachura, J .
DIGESTION, 1997, 58 (04) :319-331
[9]   Role of capsaicin-sensitive sensory nerves in gastroprotection against acid-independent and acid-dependent ulcerogens [J].
Brzozowski, T ;
Konturek, SJ ;
Sliwowski, Z ;
PytkoPolonczyk, J ;
Szlachcic, A ;
Drozdowicz, D .
DIGESTION, 1996, 57 (06) :424-432
[10]  
Brzozowski T, 1992, J Physiol Pharmacol, V43, P309