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1.
Gut ; 53(12): 1844-9, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15542526

RESUMO

BACKGROUND/AIMS: Lipopolysaccharide (LPS) induces liver injury which is associated with upregulated endothelin (ET)-1 production. The aim of this study was to investigate the effects of tezosentan, a non-selective ETA and ETB receptor antagonist, in LPS challenged rats with cirrhosis. METHODS: Rats with cirrhosis received LPS and then tezosentan or placebo one hour later. Four hours after LPS administration, rats were killed to measure serum transaminase activity and plasma tumour necrosis factor alpha (TNF-alpha) levels. Hepatic inducible nitric oxide synthase (iNOS), myeloperoxidase (MPO), a marker of neutrophil infiltration, and cyclooxygenase (COX)-2 expression were also measured. RESULTS: LPS administration significantly decreased arterial pressure and significantly increased plasma endothelin levels. Following LPS and tezosentan administration, serum aspartate aminotransferase and alanine aminotransferase activities were similar to those in the control group while they were increased by more than 700% with LPS alone. Plasma TNF-alpha levels were significantly lower in rats receiving LPS and tezosentan (182 (38) pg/ml) compared with those receiving LPS alone (821 (212) pg/ml). Tezosentan significantly decreased hepatic MPO activity and hepatic neutrophils but had no effect on LPS induced iNOS or COX-2. Survival rate was significantly higher in rats receiving LPS plus tezosentan (80%) than in rats receiving LPS alone (50%). CONCLUSION: In LPS challenged cirrhotic rats, tezosentan administration prevents LPS induced liver injury by decreasing intrahepatic neutrophil infiltration. In addition, tezosentan increases survival in these rats.


Assuntos
Antagonistas dos Receptores de Endotelina , Endotoxemia/tratamento farmacológico , Cirrose Hepática/complicações , Piridinas/uso terapêutico , Tetrazóis/uso terapêutico , Vasodilatadores/uso terapêutico , Animais , Endotelinas/sangue , Endotoxemia/complicações , Endotoxemia/metabolismo , Lipopolissacarídeos , Fígado/enzimologia , Cirrose Hepática/metabolismo , Masculino , Infiltração de Neutrófilos/efeitos dos fármacos , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Peroxidase/metabolismo , Ratos , Ratos Sprague-Dawley , Transaminases/sangue , Fator de Necrose Tumoral alfa/metabolismo
2.
J Hepatol ; 35(3): 350-7, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11592596

RESUMO

BACKGROUND/AIMS: In vitro studies have shown that cirrhotic aortas are hyporeactive to the contractile effect of vasoconstrictors because upregulated endothelial nitric oxide-synthase (NOS) overproduces nitric oxide (NO). Although stimulation of endothelial small-conductance Ca2+-dependent K+ (SK(Ca)) channels may elicit vasorelaxation in normal arteries, the role of these channels in cirrhosis-induced hyporeactivity is unknown. Thus, the aim of the present study was to investigate the role of endothelial SK(Ca) channels in cirrhosis-induced, NO-mediated, in vitro aortic hyporeactivity to alpha1-adrenergic vasoconstrictors. METHODS: Isolated thoracic aortas from cirrhotic and normal rats were used. The effects of apamin, a selective SK(Ca) channel blocker, were measured on the vascular reactivity to phenylephrine. In addition, SK(Ca) channel protein expression was studied. The effects of iberiotoxin and charybdotoxin, blockers of other K(Ca) channels, were also studied in cirrhotic aortas. RESULTS: Apamin suppressed cirrhosis-induced aortic hyporeactivity to phenylephrine in an endothelium-dependent, NOS-inhibitor-sensitive manner. SK(Ca) channel protein was overexpressed in cirrhotic aortic walls. Iberiotoxin abolished cirrhosis-induced aortic hyporeactivity to phenylephrine in an endothelium-dependent but NOS-inhibitor-resistant manner. Charybdotoxin did not induce any significant increase in phenylephrine-elicited contraction. CONCLUSIONS: In cirrhotic aortas, the overexpression and overactivity of endothelial SK(Ca) channels contributes to in vitro NO-mediated hyporeactivity to the contractile action of alpha1-adrenergic agonists.


Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Aorta/efeitos dos fármacos , Cálcio/fisiologia , Cirrose Hepática Experimental/fisiopatologia , Óxido Nítrico/fisiologia , Canais de Potássio/fisiologia , Receptores Adrenérgicos alfa 1/fisiologia , Vasoconstrição/efeitos dos fármacos , Animais , Aorta/fisiologia , Apamina/farmacologia , Charibdotoxina/farmacologia , Técnicas In Vitro , Masculino , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo III , Ratos , Ratos Sprague-Dawley
3.
J Hepatol ; 33(3): 376-81, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11019992

RESUMO

BACKGROUND/AIMS: Septic shock results in high mortality in patients with cirrhosis. Nitric oxide synthase 2 (NOS2) is induced by bacterial lipopolysaccharides (LPS) and plays a major role in the inflammatory response to bacterial infections. Little is known about the regulation of NOS2 in cirrhosis under septic conditions. Thus, the aim of this study was to determine tissue NOS2 activity, serum nitrate and tumor necrosis factor (TNF-alpha) levels and hepatic toxicity in cirrhotic rats after LPS administration. METHODS: Serum nitrates, TNF-alpha and transaminases were determined after LPS-administration in rats with secondary biliary cirrhosis and in sham-operated rats. Liver, lung, aortic and peritoneal macrophage NOS2 activities were determined by converting L[14C] arginine into L[14C] citrulline in a calcium free medium. Nitrate and TNF-alpha production were determined in a culture medium of peritoneal macrophages after in vivo LPS administration. RESULTS: LPS (1.5 mg/kg) induced 50% mortality in cirrhotic rats and no mortality in sham-operated rats. After LPS, TNF-alpha, nitrate and transaminase levels were significantly higher in cirrhotic rats compared to sham-operated rats. After LPS administration, there were no differences in NOS2 activity in the aorta, lungs, or peritoneal macrophages of the two groups, whereas NOS2 activity was significantly higher in the cirrhotic liver compared to the normal liver. CONCLUSIONS: In rats with cirrhosis, LPS administration induces higher mortality, hepatic toxicity, hepatic NOS2 activation and TNF-alpha release than in sham-operated rats. These results confirm the harmful role of septic shock in liver disease.


Assuntos
Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/intoxicação , Cirrose Hepática/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Óxido Nítrico Sintase/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Animais , Lipopolissacarídeos/toxicidade , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Masculino , Nitratos/metabolismo , Óxido Nítrico Sintase Tipo II , Ratos , Ratos Sprague-Dawley , Transaminases/sangue , Fator de Necrose Tumoral alfa/análise
4.
J Hepatol ; 33(1): 26-32, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10905582

RESUMO

BACKGROUND/AIMS: Protein kinase C plays a role in the regulation of vascular cell contraction but its activity may be reduced by nitric oxide. In portal hypertension, the exact mechanism by which nitric oxide induces vascular hyporeactivity to vasoconstrictors is unclear. The aim of this study was to investigate the role of the interaction of nitric oxide and protein kinase C in the vascular reactivity in isolated aortae from portal vein-stenosed rats. METHODS/RESULTS: The contractile response to phorbol 12,13-dibutyrate, a protein kinase C activator, was significantly reduced in portal vein-stenosed aortae compared to sham-operated aortae. Preincubation with N-nitro-L-arginine or endothelium removal enhanced the response to phorbol 12,13-dibutyrate. The hyporesponsiveness to phorbol 12,13-dibutyrate in portal vein-stenosed rat aortae was only corrected after endothelium removal. The time course of contractions induced by phorbol 12,13-dibutyrate showed that the contraction was maintained for 2 h in sham-operated aortae and decreased to baseline in portal vein-stenosed rat aortae. This decrease was inhibited by N-nitro-L-arginine preincubation or endothelium removal. Protein kinase C downregulation caused a more marked reduction of phenylephrine-induced contraction in portal vein-stenosed aortae than in sham-operated aortae. The time course of total nitric oxide synthase activity in the presence of phorbol 12,13-dibutyrate showed a decrease in nitric oxide synthase activity after 30 min in both groups. Nitric oxide synthase activity remained stable for 120 min in sham-operated aortae but returned to basal level in portal vein-stenosed aortae. CONCLUSIONS: Hyporeactivity to vasoconstrictors in portal vein-stenosed rat aortae may be due, in part, to a decrease in protein kinase C activation caused by nitric oxide overproduction.


Assuntos
Aorta/fisiopatologia , Hipertensão Portal/fisiopatologia , Óxido Nítrico/fisiologia , Proteína Quinase C/fisiologia , Vasoconstrição/fisiologia , Animais , Aorta/efeitos dos fármacos , Regulação para Baixo/fisiologia , Ativação Enzimática/fisiologia , Masculino , Óxido Nítrico Sintase/metabolismo , Dibutirato de 12,13-Forbol/farmacologia , Proteína Quinase C/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
5.
Gastroenterology ; 119(1): 196-200, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10889169

RESUMO

BACKGROUND & AIMS: In portal hypertension, the mechanisms responsible for nitric oxide (NO) overproduction and vasodilation have not yet been clearly identified. One hypothesis is that NO synthase (NOS) 3 is overactivated because of shear stress in endothelial cells caused by hyperkinetic circulation. The aim of this study was to evaluate aortic NOS3 after a reduction of blood flow by long-time beta-adrenoceptor antagonist administration. METHODS: Propranolol or atenolol was administered by gavage in portal vein-stenosed and sham-operated rats. The vascular reactivity of thoracic aortic rings to phenylephrine, total aortic NOS activity, and aortic NOS3 messenger RNA and protein expressions were studied. RESULTS: After propranolol or atenolol administration, the aortic hyporesponse returned to normal in portal vein-stenosed rats. Total aortic NOS activity was higher in portal vein-stenosed aortas and significantly decreased after beta-blocker administration. Aortic NOS3 expressions were more marked in portal vein-stenosed aortas than in controls, but NOS3 expressions were reduced after propranolol administration. CONCLUSIONS: In portal hypertension, aortic NOS3 activity and expressions are enhanced but return to normal after beta-blocker administration. These results suggest that in portal hypertension, increased shear stress, related to high blood flow, induces enhanced aortic NOS3.


Assuntos
Aorta/enzimologia , Hipertensão Portal/fisiopatologia , Óxido Nítrico Sintase/fisiologia , Vasodilatação/fisiologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Atenolol/farmacologia , Constrição Patológica , Técnicas In Vitro , Masculino , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo III , Veia Porta/fisiopatologia , Propranolol/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Valores de Referência , Vasodilatadores/farmacologia
6.
Gastroenterology ; 119(1): 201-10, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10889170

RESUMO

BACKGROUND & AIMS: Although protein kinase C (PKC) alterations may play a role in the abnormal reactivity of cirrhotic rat aortas, its isoforms and cellular distribution are unknown. We therefore studied the protein expression and cellular distribution of PKC isoforms and their activation in cirrhotic rat aortas. METHODS: Endothelium-denuded aortas from control and cirrhotic rats were examined. Immunoblots were performed with PKC isoform-specific antibodies. Aortic reactivity was determined for phorbol myristate acetate and phenylephrine after PKC down-regulation. RESULTS: PKC-alpha expression was reduced in both the cytosolic and membrane fractions in cirrhotic aortas. Trace amounts of PKC-beta were detected in cirrhotic aortas. PKC-delta was detected in the cytosolic fraction of control and cirrhotic aortas. PKC-zeta was detected in the membrane fraction in control aortas and in the cytosolic fraction in cirrhotic aortas. Phorbol myristate acetate and phenylephrine triggered translocation of PKC-alpha and PKC-delta isoforms from the cytosol to the membrane in control aortas; in cirrhotic aortas, only PKC-alpha was translocated. Aortic reactivities were reduced after PKC down-regulation. PKC-alpha and -delta activities were reduced in cirrhotic aortas. CONCLUSIONS: These results suggest that a change in PKC isoforms may be responsible in part for the abnormal reactivity and intracellular transduction through the PKC pathway in cirrhotic rat aortas.


Assuntos
Aorta/fisiopatologia , Isoenzimas/metabolismo , Cirrose Hepática Experimental/fisiopatologia , Proteína Quinase C/metabolismo , Sistema Vasomotor/fisiopatologia , Animais , Transporte Biológico/efeitos dos fármacos , Regulação para Baixo , Membranas Intracelulares/enzimologia , Masculino , Fenilefrina/farmacologia , Ratos , Ratos Sprague-Dawley , Valores de Referência , Acetato de Tetradecanoilforbol/farmacologia , Fatores de Tempo , Distribuição Tecidual , Vasoconstrição/fisiologia , Vasoconstritores/farmacologia
7.
Clin Sci (Lond) ; 97(3): 313-8, 1999 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10464056

RESUMO

In cirrhosis there is a hyperdynamic circulation, which occurs mainly in the systemic and splanchnic regions. Using isolated-vessel models, previous studies have shown reduced aortic reactivity to vasoconstrictors in rats with cirrhosis. The aim of the present study was to evaluate and compare the vascular responsiveness to phenylephrine in arterial rings and the blood flows from different regions in rats with cirrhosis and controls. Reactivity was studied in isolated thoracic aortic, superior mesenteric arterial and carotid arterial rings from sham-operated and bile-duct-ligated rats by measuring the cumulative concentration-dependent tension induced by phenylephrine (10(-9)-10(-4) M). Blood flows were measured by the radioactive microsphere method. In rats with cirrhosis, a significant hyporeactivity to phenylephrine was observed in both the aorta and the superior mesenteric artery compared with the corresponding arteries of normal rats. This hyporesponsiveness was corrected by N(omega)-nitro-L-arginine (0.1 mM). In contrast, carotid artery reactivity and the responses to N(omega)-nitro-L-arginine were similar in the cirrhotic and control groups. In each case, cardiac output and mesenteric arterial blood flow were significantly higher in cirrhotic than in normal rats. Cerebral blood flows were not significantly different between the two groups. In cirrhotic rats, arterial hyporeactivity may be a consequence of increased regional blood flow and increased production of nitric oxide.


Assuntos
Cirrose Hepática Experimental/fisiopatologia , Vasoconstrição/fisiologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiopatologia , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/fisiopatologia , Técnicas de Cultura , Hemodinâmica , Masculino , Artéria Mesentérica Superior/efeitos dos fármacos , Artéria Mesentérica Superior/fisiopatologia , Fenilefrina/farmacologia , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/fisiologia , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia
8.
Hepatology ; 30(3): 698-704, 1999 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10462376

RESUMO

Hyporeactivity to vasoconstrictors in aortae from portal vein-stenosed rats is associated with an increased activity of endothelial NO synthase (NOS3). In contrast, during sepsis, which is common in cirrhosis, vascular hyporeactivity is associated with an induction of inducible NOS2. The aim of this study was to investigate the in vitro reactivity to phenylephrine and the regulation of NOS2 and NOS3 in aortae from portal vein-stenosed rats after lipopolysaccharide (LPS) administration. Aortic vascular reactivity for phenylephrine, aortic NOS activity, and NOS2 and NOS3 protein expression were determined 5 hours after intravenous LPS or saline administration. Moreover, aortic NOS activity was measured after 5-hour in vitro incubation in LPS. LPS induced a significantly smaller decrease in aortic tension in portal vein-stenosed than in sham-operated rats. Under baseline conditions, aortic NOS activity and NOS3 protein expression were higher in portal vein-stenosed than in sham-operated rats, and NOS2 protein expression was not detected in aortae from either group. After LPS administration, NOS activity and NOS2 protein expression increased significantly less in portal vein-stenosed than in sham-operated rat aortae. Similar results were obtained after in vitro incubation with LPS. Endothelium removal or NOS3 inhibition with the calmodulin inhibitor, W7, increased NOS activity in the aortae of portal vein-stenosed rats after LPS incubation. In conclusion, in aortae of portal vein-stenosed rats exposed to LPS, no further decrease in aortic reactivity to phenylephrine was observed, and the induction of NOS2 was down-regulated. Endothelium removal or calmodulin inhibition inhibits NOS3 overactivity and leads to normalized NOS2 activation after LPS in aortae from portal vein-stenosed rats.


Assuntos
Aorta/enzimologia , Hipertensão Portal/enzimologia , Lipopolissacarídeos/farmacologia , Óxido Nítrico Sintase/metabolismo , Animais , Masculino , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III , Fenilefrina/farmacologia , Veia Porta , Ratos , Ratos Sprague-Dawley
9.
Dakar Med ; 39(1): 99-107, 1994.
Artigo em Francês | MEDLINE | ID: mdl-7493531

RESUMO

The aim of this study is: 1. to isolate intrahepatic biliary epithelial cells and, 2. to study the toxicity of cholestatic biliary acids on these cells. Cells were isolated from rats with proliferated bile duct-cells, that were induced by a 21 days bile duct ligation. They were characterized by glutamyltranspeptidase and cytokeratins 7 and 19 using histochemical or immuno cytochemical methods. Isolated cells were incubated with different concentrations (250, 500, 1000 and 2000 microM) of cholestatic biliary acids, lithocholate sulfate (LCS) and taurolithocholate sulfate (TLCS. Cells viability is estimated by three methods: Trypan blue, LDH release and MTT test. We obtained purified fractions of non parenchymal liver cells enriched in biliary epithelial cells (> 95%). On these cells, we showed toxicity of LCS and TLCS and determined CI 10 and CI 50 of these acids which were respectively 800 microM and 2 mM for LCS; 1.4 and 2 mM for TLCS. These results indicate that cholestatic biliary acids (LCS and TLCS) are toxic for biliary cells. This cytotoxicity can be probably a possible mechanism of cholestasis.


Assuntos
Ácidos e Sais Biliares/toxicidade , Ductos Biliares Intra-Hepáticos/efeitos dos fármacos , Colestase/metabolismo , Animais , Ductos Biliares Intra-Hepáticos/citologia , Morte Celular/efeitos dos fármacos , Queratinas/análise , Ligadura , Ácido Litocólico/toxicidade , Ratos , Ratos Sprague-Dawley , Ácido Taurolitocólico/toxicidade , gama-Glutamiltransferase/análise
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