RESUMO
We have reported that nicotine and the specific α7AChR agonist ameliorate indomethacin-induced intestinal lesions in mice by activating α7 nicotinic acetylcholine receptors (α7nAChR). Dopamine D2-receptor antagonists, such as domperidone and metoclopramide, enhance the release of ACh from vagal efferent nerves. The present study examined the effects of domperidone and metoclopramide on indomethacin-induced small intestinal ulceration in mice, focusing on the α7AChR. Male C57BL/6 mice were administered indomethacin (10 mg/kg, s.c.) and sacrificed 24 h later. Domperidone (0.1-10 mg/kg) and metoclopramide (0.03-0.3 mg/kg) were administered i.p. twice, at 0.5 h before and 8 h after indomethacin treatment, while methyllycaconitine (a selective antagonist of α7nAChR, 30 mg/kg) was administered twice, at 0.5 h before each domperidone treatment. Indomethacin caused severe hemorrhagic lesions in the small intestine, mostly to the jejunum and ileum, with a concomitant increase in myeloperoxidase (MPO) activity. Domperidone suppressed the severity of lesions and the increase in MPO activity at low doses (0.1-3 mg/kg), but not at a high dose (10 mg/kg). Similar effects were also observed by metoclopramide. The protective effects of domperidone and metoclopramide were totally abolished by prior administration of methyllycaconitine. Indomethacin treatment markedly enhanced inducible nitric oxide synthase and chemokine mRNA expression in the small intestine, but these responses were all significantly attenuated by either domperidone or metoclopramide. These findings suggest that dopamine D2-receptor antagonists ameliorate indomethacin-induced small intestinal ulceration through the activation of endogenous anti-inflammatory pathways mediated by α7nAChR.
Assuntos
Antiulcerosos/uso terapêutico , Antagonistas de Dopamina/uso terapêutico , Antagonistas dos Receptores de Dopamina D2 , Enteropatias/prevenção & controle , Intestino Delgado/efeitos dos fármacos , Receptores Nicotínicos/metabolismo , Úlcera/prevenção & controle , Animais , Anti-Inflamatórios não Esteroides/agonistas , Anti-Inflamatórios não Esteroides/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/toxicidade , Antiulcerosos/administração & dosagem , Antiulcerosos/efeitos adversos , Domperidona/administração & dosagem , Domperidona/efeitos adversos , Domperidona/uso terapêutico , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/efeitos adversos , Relação Dose-Resposta a Droga , Fármacos Gastrointestinais/agonistas , Fármacos Gastrointestinais/antagonistas & inibidores , Fármacos Gastrointestinais/toxicidade , Motilidade Gastrointestinal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Indometacina/agonistas , Indometacina/antagonistas & inibidores , Indometacina/toxicidade , Enteropatias/metabolismo , Enteropatias/patologia , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Masculino , Metoclopramida/administração & dosagem , Metoclopramida/efeitos adversos , Metoclopramida/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas Nicotínicos/toxicidade , Ratos , Ratos Wistar , Receptores Nicotínicos/química , Índice de Gravidade de Doença , Úlcera/metabolismo , Úlcera/patologia , Receptor Nicotínico de Acetilcolina alfa7RESUMO
Cholinergic anti-inflammatory actions have been shown to result mainly from the activation of α7 nicotinic acetylcholine receptors. Here, we investigated the possible role of α7 nicotinic acetylcholine receptors in the pathogenesis of indomethacin-induced small intestinal ulceration in mice. Male C57BL/6 mice were given indomethacin (10mg/kg, s.c.), and sacrificed 24h later. Nicotine (0.3-3mg/kg) and PNU-282987 (a selective agonist of α7 nicotinic acetylcholine receptors; 1-10mg/kg) were administered i.p. twice, at 0.5h before and 8h after indomethacin treatment, while methyllycaconitine (a selective antagonist of α7 nicotinic acetylcholine receptors; 10mg/kg was administered twice, at 0.5h before each nicotine treatment. Indomethacin caused severe hemorrhagic lesions in the small intestine with marked increases in myeloperoxidase (MPO) activity and inducible nitric oxide synthase (iNOS) expression in the mucosa. Pretreatment with nicotine reduced the severity of intestinal lesions in a dose-dependent manner. The protective effect of nicotine was mimicked by PNU-282987 and significantly attenuated by methyllycaconitine. The increases in MPO activity and iNOS expression induced by indomethacin were also significantly suppressed by nicotine and PNU-282987. Immunohistochemical study showed that the expression of α7 nicotinic acetylcholine receptors was clearly enhanced in the submucosa of the damaged area following indomethacin treatment. These results suggest that the activation of α7 nicotinic acetylcholine receptors ameliorates indomethacin-induced small intestinal ulceration, and that this effect may result from the inhibition of iNOS expression and neutrophil migration.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Indometacina/efeitos adversos , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Receptores Nicotínicos/metabolismo , Úlcera/induzido quimicamente , Úlcera/metabolismo , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Benzamidas/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Intestino Delgado/enzimologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Óxido Nítrico Sintase Tipo II/genética , Peroxidase/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tirosina/análogos & derivados , Tirosina/biossíntese , Úlcera/enzimologia , Receptor Nicotínico de Acetilcolina alfa7RESUMO
It was reported previously that non-steroidal anti-inflammatory drugs (NSAID)-induced gastric damage was markedly aggravated in rats during arthritis, and this response was mediated by the overproduction of nitric oxide (NO) derived from endothelial NO synthase (eNOS) in addition to inducible NO synthase (iNOS). The present study examined the gastric ulcerogenic response to cold-restraint stress in adjuvant arthritic rats, particularly in relation to NO/NOS isozymes. Exposure of normal rats to cold-restraint stress (13 degrees C) produced slight gastric damage 3 h later, but the ulcerogenic response was markedly aggravated in arthritic rats. Pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME) (a nonselective inhibitor of NOS) slightly increased the cold-restraint stress-induced gastric lesions in normal rats, but dose-dependently prevented the aggravation of these lesions in arthritic rats. The increased ulcerogenic response in arthritic rats was significantly suppressed by 1400 W (a selective inhibitor of iNOS) and L-iminoethyl ornithine (L-NIO) (a selective inhibitor of eNOS), but not by N(G)-propyl-L-arginine (L-NPA) (a selective inhibitor of nNOS), and almost totally abolished by the co-administration of 1400 W and L-NIO. The mucosal expression levels of eNOS and iNOS but not nNOS mRNAs were enhanced in arthritic rats compared with normal rats. The aggravation of stress-induced gastric lesions in arthritic rats was also significantly suppressed by pretreatment with glutathione. These results suggest that the gastric ulcerogenic response to cold-restraint stress is enhanced in arthritic rats, similar to that induced by NSAIDs, and this phenomenon may be causally associated with the upregulation of eNOS/NO in addition to iNOS/NO.