RESUMEN
Cyclosporin-A (CsA) has been reported to protect livers from warm ischemia/reperfusion (I/R) injury. To study if CsA has also a protective effect on cold I/R injury, two models were used: the isolated perfused rat liver (IPRL) and the orthotopic rat liver transplantation (ORLT). (1) IPRL: Livers were preserved for 24 h (5°C) in University of Wisconsin (UW) solution alone (group 1), with CsA (400 nM) dissolved in dimethylsulfoxide (50 µM) (group 2), and with dimethylsulfoxide (DMSO) alone (group 3). Livers were reperfused for 60 min (37°C) (n = 8/group). Cell necrosis was evaluated by trypan blue uptake and apoptosis by laddering and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, and by caspase-3 activation. Marked and similar sinusoidal endothelial cell necrosis was found in the three groups while apoptosis was found similarly deceased in groups 2 and 3 compared with group 1. (2) ORLT: Donors received either CsA (5 mg/kg) or corn oil 24 h before transplantation. Recipients were sacrificed after 240 min; cell necrosis and apoptosis were then evaluated. No difference was found between treated and control groups. The current data strongly suggest that CsA has no protective effect on hepatic cold I/R injury. Hepatocyte apoptosis can be reduced by antioxidants, as occurred with DMSO, but introduction of CsA does not provide additional protective effect.
Asunto(s)
Isquemia Fría , Ciclosporina/uso terapéutico , Hígado/irrigación sanguínea , Hígado/patología , Daño por Reperfusión/patología , Daño por Reperfusión/prevención & control , Adenosina/farmacología , Alopurinol/farmacología , Animales , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Ciclosporina/farmacología , Dimetilsulfóxido/farmacología , Endotelio/efectos de los fármacos , Endotelio/patología , Glutatión/farmacología , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Insulina/farmacología , Hígado/enzimología , Trasplante de Hígado/patología , Masculino , Modelos Animales , Soluciones Preservantes de Órganos/farmacología , Rafinosa/farmacología , Ratas , Ratas Endogámicas Lew , Flujo Sanguíneo Regional/fisiología , Daño por Reperfusión/enzimologíaRESUMEN
We aimed to confirm the gastrokinetic effect of ghrelin analog, RC-1139, in the presence of opiates. Gastric emptying was verified in rats by counting stomach residue 15 min after gavage of methylcellulose. Normal rats: RC-1139 (0, 0.25, 1.0, 2.5 mg/kg i.v.) decreased methylcellulose left in stomach (47, 36, 12, 10% of ingested solution). Post-operative ileus (post-op. ileus) ileus: gastric residue decreased from 88 to 66, 53, 51% with RC-1139 0, 1.0, 2.5, 10 mg/kg. Morphine in post-op. ileus: gastroparesis was corrected at 10 mg/kg (54%). Ghrelin analog RC-1139 is a potent gastrokinetic in rat; it reversed gastric post-op. ileus, even in the presence of opiates.
Asunto(s)
Vaciamiento Gástrico/efectos de los fármacos , Ileus/tratamiento farmacológico , Morfina/farmacología , Hormonas Peptídicas/farmacología , Complicaciones Posoperatorias/tratamiento farmacológico , Animales , Estado de Conciencia , Relación Dosis-Respuesta a Droga , Ileus/inducido químicamente , Masculino , Ratas , Ratas Sprague-Dawley , Receptores Acoplados a Proteínas G/agonistas , Receptores de GhrelinaRESUMEN
BACKGROUND/AIMS: Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of chronic liver disease. Brain monoamines have been implicated in the pathogenesis of HE. We examined the relationship between monoamine dysfunction and the degree of portal-systemic shunting (PSS) in rats with varying degrees of PSS. METHODS: Concentrations of catecholamines, serotonin, histamine, precursors and metabolites in frontal cortex of rats with varying degrees of PSS (9-99.8%) were measured by HPLC. RESULTS: The concentrations of the serotonin precursor, tryptophan, and its metabolite, 5-HIAA were increased up to 4-fold in brains of rats with various degrees of PSS and were significantly correlated with the degree of shunting and with arterial ammonia levels. Brain levels of histamine, its precursor, l-histidine, and metabolite, tele-methylhistamine were significantly increased only following total shunting. Concentrations of catecholamines and their metabolites were not significantly correlated with degree of PSS or hyperammonemia. CONCLUSIONS: Given the established role of the serotonin system in the regulation of sleep, circadian rhythmicity and locomotion these findings suggest that selective alterations of this system could be implicated in the pathogenesis of HE. Therapeutic approaches aimed at the normalization of serotonin turnover could be beneficial in the prevention and treatment of early neuropsychiatric symptoms of HE.