Effects of cinitapride on gastric ulceration and secretion in rats.
OBJECTIVE
The aim of the present study was to examine the effects of cinitapride, a novel prokinetic benzamide-stimulating gastrointestinal motility agent, on gastric secretion and ulceration in rats and elucidate some possible vascular and anti-oxidant mechanisms of such protection.


METHODS
Male Wistar rats.


METHODS
Cinitapride (CNT, Lab. Almirall, S.A.) (0.25, 0.5, and 1 mg/kg) and 5-hydroxytryptamine (5-HT, Sigma Chemical Co., St. Louis, MO, USA) (10 mg/kg), administered intraperitoneally (i.p.).


METHODS
Gastric ulceration was induced by instillation of 1 mL/100 g animal of 50% (v/v) ethanol in distilled water and by pylorus-ligated rat model. Gastric microvascular changes, and the activity of myeloperoxidase (as a marker of neutrophil infiltration) and glutathione peroxidase (an important enzyme in scavenging of lipid peroxides) were determined. The results were compared with those of 5-HT. The data were evaluated using Student's t-test for paired data and the non-parametric Mann-Whitney U-test.


RESULTS
In 4 h pyloric-ligated animals, i.p. CNT did not significantly reduce the incidence of gastric mucosal damage, and no significant differences were found in the values of total volume and acidity. However, CNT caused a marked and dose-dependent reduction of haemorrhagic lesions induced by 50% v/v ethanol. These protective effects were specifically related to a reduction of neutrophil infiltration. CNT at the dose of 1 mg/kg raised the decreased glutathione peroxidase activity to the control level. In contrast, pretreatment with 5-HT worsened the ethanol-induced erosions, but did not significantly induce any gastric microvascular changes. However, the myeloperoxidase activity rose markedly and the glutathione peroxidase levels decreased significantly in the mucosa injured by 50% v/v ethanol.


CONCLUSIONS
This study demonstrates a new gastroprotective feature of CNT that could be partly explained not only through reduction of neutrophil toxicity but also by an increased synthesis of free-radical scavenging enzymes such as glutathione peroxidase. Furthermore, it is likely that serotonergic-dependent mechanisms are also involved via 5-HT2-receptor blockade and 5-HT1 receptor activation.
Alarcón de la Lastra
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Departamento de Farmacología, Facultad de Farmacia, Universidad de Sevilla, Spain. Alarcon@fafar.us.es
La Casa
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Martin
M J
MJ
Motilva
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V
D000818:Animals; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001549:Benzamides / Q000008:administration & dosage / Q000627:therapeutic use*; D002199:Capillary Permeability / Q000187:drug effects; D000431:Ethanol; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects; D005769:Gastrointestinal Motility / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000032:analysis; D007274:Injections, Intraperitoneal; D008297:Male; D009195:Peroxidase / Q000032:analysis; D011708:Pylorus; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism
D000897:Anti-Ulcer Agents; D001549:Benzamides; D011985:Receptors, Serotonin; D000431:Ethanol; D009195:Peroxidase; D005979:Glutathione Peroxidase; C045316:cinitapride