RESUMEN
BACKGROUND: Microcirculatory disturbance has been shown to play a critical role in hepatic ischemia and reperfusion (I/R) injury. Angiotensin II (AngII) is one of the most potent endogenous vasoconstrictors. Angiotensin II type I (AT1) receptor antagonist has been reported to have protective effects on I/R injury of the heart and kidney. However, effect on hepatic I/R injury has not been determined. In this study, we investigate our hypothesis that AT1 receptor antagonist, CV-11974, attenuates hepatic I/R injury. METHODS: Twelve beagle dogs underwent a 2-hr total hepatic vascular exclusion with veno-venous bypass. CV-11974 was given to animals at a dose of 0.002 mg/ kg/min for 5 min followed by 0.001 mg/kg/min for 25 min via portal vein before ischemia (group II, n=6). Nontreated animals were used as the control (group I, n=6). Animal survival, hemodynamics, hepatic tissue blood flow (HTBF), liver function, platelet count, renin activity, and AngII concentration of hepatic vein, energy metabolism, and histopathology were analyzed. RESULTS: Two-week survival was 33% in group I, in contrast, 100% in group II. Mean arterial blood pressure during early reperfusion was maintained, and HTBF after reperfusion was significantly higher in group II. Treatment attenuated liver enzyme release and decrease of platelet count, increased renin and AngII, suppressed ATP degradation during ischemia and enhanced ATP resynthesis after reperfusion. Neutrophil infiltration and histopathological damages were lessened in group II. CONCLUSIONS: Our data demonstrated that the local renin-angiotensin system might play a role in hepatic microcirculation. AT1 receptor blockade with CV-11974 attenuated hepatic microcirculatory disturbance and ameliorated I/R injury.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Bencimidazoles/farmacología , Hemodinámica/fisiología , Isquemia/fisiopatología , Circulación Hepática/fisiología , Hígado/irrigación sanguínea , Daño por Reperfusión/prevención & control , Tetrazoles/farmacología , Angiotensina II/sangre , Animales , Aspartato Aminotransferasas/sangre , Compuestos de Bifenilo , Presión Sanguínea/efectos de los fármacos , Perros , Femenino , Hemodinámica/efectos de los fármacos , Venas Hepáticas , Hígado/fisiología , Circulación Hepática/efectos de los fármacos , Pruebas de Función Hepática , Receptor de Angiotensina Tipo 1 , Receptor de Angiotensina Tipo 2 , Flujo Sanguíneo Regional/efectos de los fármacos , Renina/sangre , Factores de TiempoRESUMEN
BACKGROUND: Membrane phospholipid breakdown, caused by ischemia and reperfusion (I/R) of the liver, releases free fatty acids including arachidonic acids and lysophospholipids, which serve as precursors of various inflammatory lipid derivatives. Phospholipase A2 (PLA2) is a key enzyme that initiates this reaction. In this study, we tested our hypothesis that a type II PLA2 inhibitor, LY329722, could attenuate hepatic I/R injury caused by a 2-hr total hepatic vascular exclusion (THVE) in dogs. METHODS: Eighteen beagle dogs, subjected to a 2-hr THVE, were divided into three groups. Group 1 (n=6) was untreated and served as a control group. LY329722 was administered to animals in group 2 (n=6) intravenously (0.2 mg x kg(-1) x hr(-1)) for 60 min before ischemia, and to animals in group 3 (n=6) for 60 min starting 15 min before reperfusion (0.2 mg x kg(-1) x hr(-1)). Animal survival, systemic and splanchnic hemodynamics, hepatic tissue blood flow, liver functions, energy metabolism, hepatic venous thromboxane B2 and endothelin-1 levels, phospholipid levels and tumor necrosis factor-a mRNA expression in liver tissue, and histopathologic findings were evaluated. RESULTS: Two-week animal survival was 33% (two of six) in group 1, and 100% (six of six) in groups 2 and 3. LY329722 improved systemic and splanchnic hemodynamics, hepatic tissue blood flow, and energy metabolism, reduced liver enzyme, thromboxane B2, and endothelin-1 release, prevented hepatic phospholipid degradation and tumor necrosis factor-alpha mRNA expression, and lessened histopathologic damage and the number of neutrophil infiltrating into the liver tissue. CONCLUSION: The present study demonstrated that a type II PLA2 inhibitor, LY329722, attenuated hepatic I/R injury caused by a 2-hr THVE model in dogs.
Asunto(s)
Acetatos/farmacología , Inhibidores Enzimáticos/farmacología , Hemodinámica/fisiología , Indoles/farmacología , Isquemia/fisiopatología , Hígado/irrigación sanguínea , Fosfolipasas A/antagonistas & inhibidores , Daño por Reperfusión/prevención & control , Animales , Dinoprost/sangre , Perros , Endotelina-1/sangre , Metabolismo Energético , Inhibidores Enzimáticos/farmacocinética , Femenino , Hemodinámica/efectos de los fármacos , Isquemia/prevención & control , Hígado/fisiología , Hígado/fisiopatología , Circulación Hepática/efectos de los fármacos , Circulación Hepática/fisiología , Pruebas de Función Hepática , Fosfolipasas A2 , Flujo Sanguíneo Regional , Circulación Esplácnica/efectos de los fármacos , Circulación Esplácnica/fisiología , Tromboxano B2/sangre , Factores de Tiempo , Transcripción Genética/genética , Factor de Necrosis Tumoral alfa/genéticaAsunto(s)
Trasplante de Hígado/fisiología , Hígado/irrigación sanguínea , Sistema Renina-Angiotensina/fisiología , Daño por Reperfusión/fisiopatología , Animales , Antihipertensivos/farmacología , Bencimidazoles/farmacología , Compuestos de Bifenilo , Humanos , L-Lactato Deshidrogenasa/sangre , L-Lactato Deshidrogenasa/efectos de los fármacos , Hígado/fisiopatología , Masculino , Sistema Porta/efectos de los fármacos , Sistema Porta/fisiología , Ratas , Ratas Endogámicas Lew , Tetrazoles/farmacologíaAsunto(s)
Acetatos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Indoles/uso terapéutico , Hígado/irrigación sanguínea , Fosfolipasas A/antagonistas & inhibidores , Daño por Reperfusión/prevención & control , Animales , Presión Sanguínea/efectos de los fármacos , Perros , Evaluación Preclínica de Medicamentos , Femenino , Fosfolipasas A2 Grupo II , SístoleAsunto(s)
Dipiridamol/farmacología , Hígado/irrigación sanguínea , Daño por Reperfusión/prevención & control , Vasodilatadores/farmacología , Adenosina Trifosfato/metabolismo , Animales , AMP Cíclico/metabolismo , Perros , Evaluación Preclínica de Medicamentos , Femenino , Isquemia/tratamiento farmacológico , Hígado/metabolismo , Daño por Reperfusión/metabolismoAsunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , AMP Cíclico/metabolismo , Inhibidores Enzimáticos/farmacología , Hígado/irrigación sanguínea , Inhibidores de Fosfodiesterasa/farmacología , Daño por Reperfusión/prevención & control , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3 , Perros , Femenino , Hígado/metabolismo , Daño por Reperfusión/metabolismoAsunto(s)
Trasplante de Hígado/fisiología , Hígado/anatomía & histología , Hígado/irrigación sanguínea , Donadores Vivos , Vena Porta/fisiología , Complicaciones Posoperatorias/etiología , Adolescente , Adulto , Factores de Edad , Niño , Preescolar , Arteria Hepática/fisiología , Humanos , Lactante , Modelos Lineales , Hígado/fisiopatología , Persona de Mediana Edad , Complicaciones Posoperatorias/fisiopatología , Flujo Sanguíneo Regional , Trasplante HomólogoRESUMEN
1. Twenty centers in Japan performed 308 living donor liver transplants (LDLT) in adults. 2. Right lobe grafts were used in the minority of cases (27.1%); most had left lobe grafts (72.9%). Survival was not influenced by the type of graft. 3. There were no donor deaths (0%); 9.3% of donors experienced mild to moderate complications. Biliary complications were the most frequent. 4. Overall recipient survival was 72.4%.
Asunto(s)
Trasplante de Hígado , Donadores Vivos , Adulto , Humanos , Japón , Trasplante de Hígado/estadística & datos numéricos , Donadores Vivos/estadística & datos numéricos , Morbilidad , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: The immunosuppressive effect and other properties of a novel immunosuppressant, FTY720, have been studied mostly in the experimental transplantation of various extrahepatic organs. In this experiment, we evaluated the antirejection potency and adverse effects of this agent on liver grafts using a canine liver transplantation model. METHODS: Forty-eight orthotopic liver transplantations were performed by the standard technique under a veno-venous bypass. Liver recipients were divided into two studies: a single-dose study with FTY720 at various doses and a combined dose study with conventional immunosuppressants (cyclosporine or tacrolimus) alone and combined with FTY720. Survival, biochemical and hematological tests, blood levels of immunosuppressants, and postmortem histology were determined. RESULTS: The median survival of untreated control animals was 9 days, whereas treatment with FTY720 at a dose of 0.1 mg/kg/day prolonged graft survival to 49.5 days. FTY720 at 1 mg/kg/day showed a slight but insignificant prolongation to 16 days, but when the dose was increased to 5 mg/kg/day, the graft was rejected at 10 days. The combination of FTY720, 0.1 mg/kg/day, with a subtherapeutic dose of cyclosporine, 5 mg/kg/ day, prolonged median animal survival from 40 days with cyclosporine alone to 74 days. A combination of FTY720 (0.1 mg/kg/day) with tacrolimus (0.5 mg/kg/ day) compromised animal survival, reducing survival from 83.5 days with tacrolimus alone to 30.5 days due to infectious complication and emaciation by overimmunosuppression. No evident drug-induced side effects were observed. CONCLUSIONS: FTY720 has a potent immunosuppressive effect when used alone at 0.1 mg/kg/day in canine liver transplantation. FTY720 is a promising candidate for future clinical application in orthotopic liver transplantation.
Asunto(s)
Inmunosupresores/uso terapéutico , Trasplante de Hígado/inmunología , Glicoles de Propileno/uso terapéutico , Animales , Bilirrubina/sangre , Ciclosporina/uso terapéutico , Perros , Quimioterapia Combinada , Femenino , Clorhidrato de Fingolimod , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Trasplante de Hígado/mortalidad , Trasplante de Hígado/fisiología , Esfingosina/análogos & derivados , Tasa de Supervivencia , Tacrolimus/uso terapéutico , Factores de TiempoAsunto(s)
Supervivencia de Injerto/efectos de los fármacos , Inmunosupresores/uso terapéutico , Trasplante de Riñón/inmunología , Recuento de Linfocitos/efectos de los fármacos , Glicoles de Propileno/uso terapéutico , Animales , Perros , Clorhidrato de Fingolimod , Supervivencia de Injerto/inmunología , Esfingosina/análogos & derivados , Factores de TiempoAsunto(s)
Circulación Hepática/efectos de los fármacos , Hígado/irrigación sanguínea , Metacrilatos/farmacología , Daño por Reperfusión/prevención & control , Tromboxano-A Sintasa/antagonistas & inhibidores , 6-Cetoprostaglandina F1 alfa/sangre , Alanina Transaminasa/sangre , Animales , Presión Sanguínea/efectos de los fármacos , Perros , Inhibidores Enzimáticos/farmacología , Femenino , Isquemia/fisiopatología , Vena Porta/efectos de los fármacos , Vena Porta/fisiología , Vena Porta/fisiopatología , Flujo Sanguíneo Regional/efectos de los fármacos , Tromboxano A2/sangreAsunto(s)
Arginina/farmacología , Isquemia/fisiopatología , Circulación Hepática/fisiología , Hígado/irrigación sanguínea , Óxido Nítrico/fisiología , Daño por Reperfusión/prevención & control , Alanina Transaminasa/sangre , Animales , Perros , Femenino , Circulación Hepática/efectos de los fármacos , Neutrófilos/fisiología , Flujo Sanguíneo Regional/efectos de los fármacos , Reperfusión , Factores de TiempoAsunto(s)
Supervivencia de Injerto/inmunología , Inmunosupresores/uso terapéutico , Trasplante de Riñón/inmunología , Glicoles de Propileno/uso terapéutico , Análisis de Varianza , Animales , Perros , Relación Dosis-Respuesta a Droga , Clorhidrato de Fingolimod , Supervivencia de Injerto/efectos de los fármacos , Pruebas de Función Renal , Trasplante de Riñón/fisiología , Recuento de Linfocitos/efectos de los fármacos , Esfingosina/análogos & derivados , Trasplante HomólogoRESUMEN
BACKGROUND: The suppressed production of nitric oxide (NO), associated with endothelial dysfunction, is thought to be a cause of ischemia and reperfusion injury of the liver. But findings of the salutary effects of NO enhancement on such injury have been conflicting. In this study, we tested our hypothesis that NO enhancement would attenuate ischemic liver injury. For this purpose, an NO precursor, L-arginine, and a novel NO donor, FK409, were applied to a 2-hour total hepatic vascular exclusion model in dogs. STUDY DESIGN: L-arginine was administered IV at a dose of 100 mg/kg twice (n = 5), while 300 mg/kg twice of FK409 was infused continuously into the portal vein (n = 5). The drugs were given to the animals for 30 and 60 minutes before and after ischemia, respectively. Non-treated animals were used as the control (n = 10). Two-week survival, systemic and hepatic hemodynamics indices, liver function tests, energy metabolism, and histopathology were analyzed. RESULTS: Both treatments comparably augmented hepatic tissue blood flow, decreased liver enzyme release, and increased high-energy phosphate restoration during the reperfusion period, all of which contributed to rescuing all of the treated animals from the 2-hour total hepatic ischemia. In contrast, ischemia caused 70% mortality in the control group. Histologically, structural abnormality and neutrophil infiltration were markedly attenuated by the treatments. Systemic hypotension was observed in the animals treated with FK409, however. CONCLUSIONS: Our data demonstrate that NO enhancement alleviates the liver injury caused by ischemia and reperfusion. The supplementation of L-arginine, rather than FK409, is considered more applicable to clinical use because of the absence of systemic adverse effects.
Asunto(s)
Hígado/irrigación sanguínea , Óxido Nítrico/fisiología , Daño por Reperfusión/fisiopatología , Nucleótidos de Adenina/sangre , Alanina Transaminasa/sangre , Animales , Arginina/farmacología , Aspartato Aminotransferasas/sangre , Ácidos y Sales Biliares/sangre , Perros , Femenino , Ácido Hialurónico/sangre , L-Lactato Deshidrogenasa/sangre , Hígado/metabolismo , Hígado/patología , Donantes de Óxido Nítrico/farmacología , Nitrocompuestos/farmacología , Flujo Sanguíneo Regional/efectos de los fármacos , Daño por Reperfusión/patologíaRESUMEN
BACKGROUND: Prostaglandin has been reported to have protective effects against liver injury. Use of this agent in clinical settings, however, is limited because of drug-related side effects. This study investigated whether misoprostol, prostaglandin E1 analogue, and OP-41483, prostaglandin I2 analogue, which have fewer adverse effects with a longer half-life, attenuate ischemic liver damage. STUDY DESIGN: Thirty beagle dogs underwent 2 hours of hepatic vascular exclusion using venovenous bypass. Misoprostol was administered intravenously for 30 minutes before ischemia and for 3 hours after reperfusion. OP-41483 was administered intraportally for 30 minutes before ischemia (2 microg/kg/min) and for 3 hours after reperfusion (0.5 microg/kg/min). Animals were divided into five groups: untreated control group (n=10); high-dose misoprostol (total 100 microg/kg) group (MP-H, n=5); middle-dose misoprostol (50 microg/kg) group (MP-M, n=5); low-dose misoprostol (25 microg/kg) group (MP-L, n=5); and OP-41483 group (OP, n=5). Animal survival, hepatic tissue blood flow (HTBF), liver function, and histology were analyzed. RESULTS: Two-week animal survival rates were 30% in control, 60% in MP-H, 100% in MP-M, 80% in MP-L, and 100% in OP. The treatments with prostaglandin analogues improved HTBF, and attenuated liver enzyme release, adenine nucleotrides degradation, and histologic abnormalities. In contrast to the MP-H animals that exhibited unstable cardiovascular systems, the MP-M, MP-L, and OP animals experienced only transient hypotension. CONCLUSIONS: These results indicate that misoprostol and OP-41483 prevent ischemic liver damage, although careful dose adjustment of misoprostol is required to obtain the best protection with minimal side effects.
Asunto(s)
Epoprostenol/análogos & derivados , Isquemia/prevención & control , Hígado/irrigación sanguínea , Misoprostol/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Prostaglandinas Sintéticas/uso terapéutico , Análisis de Varianza , Animales , Perros , Relación Dosis-Respuesta a Droga , Epoprostenol/administración & dosificación , Epoprostenol/uso terapéutico , Epoprostenol/toxicidad , Femenino , Hígado/patología , Hígado/fisiopatología , Pruebas de Función Hepática , Misoprostol/administración & dosificación , Misoprostol/toxicidad , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/toxicidad , Prostaglandinas Sintéticas/administración & dosificación , Prostaglandinas Sintéticas/toxicidad , Daño por Reperfusión/prevención & controlRESUMEN
BACKGROUND: Enhanced production of endothelin-1 (ET-1), vasoconstrictive 21 amino acids produced by endothelial cells during ischemia and after reperfusion of the liver, is known to cause sinusoidal constriction and microcirculatory disturbances, which lead to severe tissue damage. Using a 2-hour hepatic vascular exclusion model in dogs, we tested our hypothesis that neutralization of ET-1 by monoclonal anti-ET-1 and anti-ET-2 antibody (AwETN40) abates vascular dysfunction and ameliorates ischemia/reperfusion injury of the liver. STUDY DESIGN: After skeletonization, the liver was made totally ischemic by cross-clamping the portal vein, the hepatic artery, and the vena cava (above and below the liver). Veno-venous bypass was used to decompress splanchnic and inferior systemic congestion. AwETN40, 5 mg/kg, was administered intravenously 10 minutes before ischemia (treatment group, n = 5). Nontreated animals were used as controls (control group, n = 10). Animal survival, hepatic tissue blood flow, liver function tests, total bile acid, high-energy phosphate, ET-1 levels, and liver histopathology were studied. RESULTS: Treatment with AwETN40 improved 2-week animal survival from 30% to 100%. Hepatic tissue blood flow after reperfusion was significantly higher in the treatment group. The treatment significantly attenuated liver enzyme release, total bile acid, and changes in adenine nucleotides. Immunoreactive ET-1 levels in the hepatic venous blood of the control group showed a significant increase and remained high for up to 24 hours after reperfusion. Histopathologic alterations were significantly lessened in the treatment group. CONCLUSIONS: These results indicate that ET-1 is involved in ischemia/reperfusion injury of the liver, which can be ameliorated by the monoclonal anti-ET-1 and anti-ET-2 antibody AwETN40.