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1.
Cyclooxygenase-derived products modulate the increased intrahepatic resistance of cirrhotic rat livers 总被引:3,自引:0,他引:3
Graupera M García-Pagán JC Abraldes JG Peralta C Bragulat M Corominola H Bosch J Rodés J 《Hepatology (Baltimore, Md.)》2003,37(1):172-181
In cirrhotic livers, increased resistance to portal flow, in part due to an exaggerated response to vasoconstrictors, is the primary factor in the pathophysiology of portal hypertension. Our aim was to evaluate the response of the intrahepatic circulation of cirrhotic rat livers to the alpha(1)-adrenergic vasoconstrictor methoxamine and the mechanisms involved in its regulation. A portal perfusion pressure dose-response curve to methoxamine was performed in control and cirrhotic rat livers preincubated with vehicle, the nitric oxide synthase blocker N(G)-nitro-L-arginine (L-NNA), indomethacin cyclooxygenase (COX) inhibitor, L-NNA + indomethacin, or the thromboxane (TX) A(2) receptor blocker SQ 29,548. TXA(2) production, COX-1 and COX-2 mRNA expression, and immunostaining for TXA(2) synthase were evaluated. Cirrhotic livers exhibited a hyperresponse to methoxamine associated with overexpression of COX-2 and TXA(2) synthase as well as with increased production of TXA(2). The hyperresponse to methoxamine of cirrhotic livers disappeared by COX inhibition with indomethacin but not after NO inhibition. SQ 29,548 also corrected the hyperresponse of cirrhotic livers to methoxamine. In conclusion, COX-derived prostanoids, mainly TXA(2), play a major role in regulating the response of cirrhotic livers to methoxamine. 相似文献
2.
Morales-Ruiz M Cejudo-Martín P Fernández-Varo G Tugues S Ros J Angeli P Rivera F Arroyo V Rodés J Sessa WC Jiménez W 《Gastroenterology》2003,125(2):522-531
Background & Aims:
Portal hypertension in cirrhosis is secondary to an increase in hepatic resistance that occurs mainly through collagen deposition. However, recent evidence points to a major contribution by other factors, such as an intrahepatic reduction in nitric oxide production. Akt is a major activator of the endothelial nitric oxide synthase (eNOS) enzyme, but its potential role in intrahepatic resistance in cirrhosis is unknown. For this reason the aims of the present study were to determine whether there is an impaired Akt activation in cirrhotic livers and how this phenomenon relates to the decrease in NO production associated with portal hypertension.Methods:
Cirrhosis was induced in rats by carbon tetrachloride inhalation. Protein abundance and phosphorylation status of Akt and eNOS were examined by Western blotting. The role of Akt in the liver of cirrhotic rats was investigated through infection with adenoviruses encoding either β-galactosidase (β-gal) or constitutively active Akt (myr-Akt).Results:
The liver of cirrhotic animals showed a significant reduction in Akt and eNOS phosphorylation. Adenoviral delivery of myr-Akt restored eNOS phosphorylation and increased the intrahepatic concentration of guanosine 3′,5′-cyclic monophosphate. These events were associated with normalization in portal pressure and a significant increase in mean arterial pressure after 3 days of adenoviral infection. In contrast, transduction of livers with β-gal did not produce any change in these hemodynamic parameters.Conclusions:
myr-Akt gene therapy restored Akt activation and NO production in the cirrhotic liver, suggesting that this therapy may be useful for the treatment of portal hypertension. 相似文献3.
Dudenhoefer AA Loureiro-Silva MR Cadelina GW Gupta T Groszmann RJ 《Hepatology (Baltimore, Md.)》2002,36(2):381-385
Nitroglycerin (NTG), a nitric oxide (NO) donor, has been shown to reduce portal pressure in cirrhotic patients. Using the in situ perfusion of normal and cirrhotic rat livers, we compared the vascular relaxation induced by either NTG or the spontaneous nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP). Normal and cirrhotic livers were perfused (40 mL/min, 37 degrees C) with Krebs' solution in a recirculating system. After preconstriction with methoxamine (10(-4) mol/L), a dose-response study was performed using 6 cumulative doses of NTG or SNAP (10(-7) to 3 x 10(-5) mol/L). NO(x) (NO(-)(2) + NO(-)(2) production in the perfusate was measured by chemiluminescence. Cirrhotic livers exhibited lower vasorelaxant responses, compared with normal livers, to both NTG (P <.0001) and SNAP (P =.0020). In normal livers, NTG and SNAP induced similar vasorelaxant responses (P =.44). In cirrhotic livers, NTG induced less vasorelaxation than SNAP (P <.0001). In the presence of NTG (P =.0045), but not SNAP (P =.99), NO(x) production in experiments with cirrhotic livers was lower than in experiments with normal livers. In conclusion, in cirrhotic rat livers, the vasorelaxant response to NTG is impaired owing to both a decreased metabolism of this NO donor and an inability of the hepatic vasculature to respond to NO. 相似文献
4.
Abstract: A method to isolate and cultivate macrophages from macronodular-cirrhotic rat livers was developed in order to characterize them biochemically, by comparing various functional parameters in macrophage cell cultures from controls and cirrhotic livers. Cells were prepared from female Wistar rats, made cirrhotic by treatment with thioacetamide, by means of a pronase-collagenase digestion method followed by a nycodenz gradient and elutriation. The yield of macrophages was 8.9×106 cells/g for controls and 10.6×106 cells/g for cirrhotic livers. The vitality of the cells was >95%. Forty-eight hours after cultivation, the purity of the cell fractions amounted to 94% and 91% in controls and in the experimental group, respectively. Nitric oxide synthesis was more markedly stimulated by lipopolysaccharide (LPS) in cultures from cirrhotic livers than in those from controls (25×4 vs 5.8×1 nmol/106 cells/72 hours). Interferon-gamma (IFN-γ) induced the nitric oxide synthase more rapidly in macrophage cultures from cirrhotic livers than in controls. The production of superoxide anions by macrophages from cirrhotic livers stimulated by zymosan was significantly lower by about 40% when compared with the controls. Incorporation of 3H-thymidine was increased to 250% in cultivated macrophages from thioacetamide-treated rats in comparison with macrophages from untreated animals. The stimulated phagocytic activity of cultivated macrophages from cirrhotic livers did not differ significantly from that of the controls. The data presented provide evidence that it is possible to isolate and to cultivate macrophages from macronodular-cirrhotic livers with high yield and vitality. They are characterized by enhanced proliferation, reduced formation of superoxide anions, and increased production of nitric oxide. 相似文献
5.
Gracia-Sancho J Laviña B Rodríguez-Vilarrupla A Brandes RP Fernández M Bosch J García-Pagán JC 《Gastroenterology》2007,133(3):959-966
BACKGROUND & AIMS: Increased hepatic vascular resistance in cirrhosis is in part due to reduced nitric oxide (NO) bioavailability. This is related to insufficient NO synthesis from endothelial nitric oxide synthase and to enhanced NO scavenging by superoxide radicals (O(2)(-)). Nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase is an important source of O(2)(-) that increases vascular tone in different cardiovascular disorders. Thus, our aims were to study the molecular and biochemical state of NADPH-oxidase in cirrhotic livers and to investigate its possible role in modulating hepatic vascular tone in cirrhosis. METHODS: NADPH-oxidase expression and enzymatic activity were determined in control (n = 8) and CCl(4)-cirrhotic (n = 8) rat livers. Additional control (n = 6) and CCl(4)-cirrhotic (n = 10) rats were treated with apocynin (a selective NADPH-oxidase inhibitor) or its vehicle. Mean arterial pressure, portal pressure, and superior mesenteric arterial blood flow were measured in vivo. Moreover, hepatic endothelial function was evaluated in isolated and perfused rat livers by dose-response curves to acetylcholine. In addition, in 6 control and 6 cirrhotic human livers NADPH-oxidase activity and expression were evaluated. RESULTS: Rat cirrhotic livers had no increased NADPH-oxidase protein expression or activity in relation to control livers. NADPH-oxidase inhibition did not modify splanchnic or systemic hemodynamics in control or cirrhotic rats and did not improve the impaired endothelial-dependent vasodilatory response to acetylcholine of cirrhotic livers. Human cirrhotic livers also did not exhibit increased NADPH-oxidase expression or activity. CONCLUSIONS: Our study shows that NADPH-oxidase activity is decreased in the cirrhotic livers and therefore cannot explain increased hepatic O(2)(-), endothelial dysfunction, and increased vascular tone in cirrhotic livers. 相似文献
6.
Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase 总被引:4,自引:0,他引:4
Trebicka J Hennenberg M Laleman W Shelest N Biecker E Schepke M Nevens F Sauerbruch T Heller J 《Hepatology (Baltimore, Md.)》2007,46(1):242-253
In cirrhosis, increased RhoA/Rho-kinase signaling and decreased nitric oxide (NO) availability contribute to increased intrahepatic resistance and portal hypertension. Hepatic stellate cells (HSCs) regulate intrahepatic resistance. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) inhibit synthesis of isoprenoids, which are necessary for membrane translocation and activation of small GTPases like RhoA and Ras. Activated RhoA leads to Rho-kinase activation and NO synthase inhibition. We therefore investigated the effects of atorvastatin in cirrhotic rats and isolated HSCs. Rats with secondary biliary cirrhosis (bile duct ligation, BDL) were treated with atorvastatin (15 mg/kg per day for 7 days) or remained untreated. Hemodynamic parameters were determined in vivo (colored microspheres). Intrahepatic resistance was investigated in in situ perfused livers. Expression and phosphorylation of proteins were analyzed by RT-PCR and immunoblots. Three-dimensional stress-relaxed collagen lattice contractions of HSCs were performed after incubation with atorvastatin. Atorvastatin reduced portal pressure without affecting mean arterial pressure in vivo. This was associated with a reduction in intrahepatic resistance and reduced responsiveness of in situ-perfused cirrhotic livers to methoxamine. Furthermore, atorvastatin reduced the contraction of activated HSCs in a 3-dimensional stress-relaxed collagen lattice. In cirrhotic livers, atorvastatin significantly decreased Rho-kinase activity (moesin phosphorylation) without affecting expression of RhoA, Rho-kinase and Ras. In activated HSCs, atorvastatin inhibited the membrane association of RhoA and Ras. Furthermore, in BDL rats, atorvastatin significantly increased hepatic endothelial nitric oxide synthase (eNOS) mRNA and protein levels, phospho-eNOS, nitrite/nitrate, and the activity of the NO effector protein kinase G (PKG). CONCLUSION: In cirrhotic rats, atorvastatin inhibits hepatic RhoA/Rho-kinase signaling and activates the NO/PKG-pathway. This lowers intrahepatic resistance, resulting in decreased portal pressure. Statins might represent a therapeutic option for portal hypertension in cirrhosis. 相似文献
7.
Lien Van Landeghem Wim Laleman Ingrid Vander Elst Marcel Zeegers Jos Van Pelt David Cassiman Frederik Nevens 《Liver international》2009,29(5):650-660
Background/Objective: Carbon monoxide (CO) produced by haem‐oxygenase isoforms (HO‐1 & HO‐2) is involved in the regulation of systemic vascular tone. We aimed to elucidate the vasoregulatory role of CO in the microcirculation in normal and thioacetamide cirrhotic rat livers. Methods: Haem‐oxygenase expression was examined by Western blot. Total HO enzymatic activity was measured spectrophotometrically. Sensitivity of hepatic stellate cells (HSCs) to CO‐mediated relaxation was studied by a stress‐relaxed‐collagen‐lattice model. To define the relative role of CO, the CO‐releasing molecule CORM‐2, the HO‐inhibitor zinc protoporphyrin‐IX and the HO‐1 inducer hemin were added to an in situ liver perfusion set‐up. The topography of vasoactive CO production was evaluated by applying different CO‐ and nitric oxide‐trapping reagents in the liver perfusion set‐up and by immunohistochemistry. Results: Western blot showed decreased expression of both HO isoenzymes (P<0.036 for HO‐1; P<0.001 for HO‐2) in cirrhotic vs normal rat livers, confirmed by the HO‐activity assay (P=0.004). HSCs relaxed on exposure to CORM‐2 (P=0.013). The increased intrahepatic vascular resistance (IHVR) of cirrhotic rats was attenuated by perfusion with CORM‐2 (P=0.016) and pretreatment with hemin (P<0.001). Inhibition of HO caused a dose‐related increase in IHVR in normal and cirrhotic liver. In normal liver, the haemodynamically relevant CO production occurred extrasinusoidally, while intrasinusoidally HO‐1 predominantly regulated the microcirculation in cirrhotic livers. Conclusion: We demonstrate a role for CO and HO in the regulation of normal and cirrhotic microcirculation. These findings are of importance in the pathophysiology of portal hypertension and establish CO/HO as novel treatment targets. 相似文献
8.
Ferdinand Serracino-Inglott Ioannis T Virlos Nagy A Habib Robin CN Williamson Robert T Mathie 《BMC gastroenterology》2002,2(1):22-6
Background
Previous work has suggested that in the liver, adenosine preconditioning is mediated by nitric oxide. Whether the endothelial isoform of nitric oxide synthase plays a part in this mechanism has however not yet been investigated.Methods
Wistar rats were used (6 in each group) – Groups: (1) sham, (2) ischemia-reperfusion, (3) adenosine + ischemia-reperfusion, (4) endothelial isoform inhibitor + adenosine + ischemia-reperfusion.Results
Using immunohistochemistry, this study has revealed a decrease in the expression of endothelial nitric oxide synthase following hepatic ischemia-reperfusion. This was prevented by adenosine pre-treatment. When an inhibitor of endothelial nitric oxide synthase was administered prior to adenosine pre-treatment, pre-conditioning did not occur despite normal expression of endothelial nitric oxide synthase.Conclusions
These findings suggest that adenosine attenuates hepatic injury by preventing the downregulation of endothelial nitric oxide synthase that occurs during ischemia-reperfusion. 相似文献9.
In vivo gene transfer of endothelial nitric oxide synthase decreases portal pressure in anaesthetised carbon tetrachloride cirrhotic rats 总被引:14,自引:0,他引:14
BACKGROUND: Portal hypertension in cirrhosis results from enhanced intrahepatic resistance to an augmented inflow. The former is partly due to an imbalance between intrahepatic vasoconstriction and vasodilatation. Enhanced endothelin-1 and decreased activity of hepatic constitutive endothelial nitric oxide synthase (NOS 3) was reported in carbon tetrachloride (CCl(4)) cirrhotic rat liver. AIMS: To study whether an increase in hepatic NOS 3 could be obtained in the CCl(4) cirrhotic rat liver by in vivo cDNA transfer and to investigate a possible effect on portal pressure. METHODS: Hepatic NOS 3 immunohistochemistry and western blotting were used to measure the amount of NOS 3 protein. Recombinant adenovirus, carrying cDNA encoding human NOS 3, was injected into the portal vein of CCl(4) cirrhotic rats. Cirrhotic controls received carrier buffer, naked adenovirus, or adenovirus carrying the lac Z gene. RESULTS: NOS 3 immunoreactivity and amount of protein (western blotting) were significantly decreased in CCl(4) cirrhotic livers. Following cDNA transfer, NOS 3 expression and the amount of protein were partially restored. Portal pressure was 11.4 (1.6) mm Hg in untreated cirrhotic (n=9) and 11.8 (0.6) in lac Z transfected (n=4) cirrhotic rats but was reduced to 7.8 (1.0) mm Hg (n=9) five days after NOS 3 cDNA transfer. No changes were observed in systemic haemodynamics, in liver tests or urinary nitrates, or in NOS 3 expression in lung or kidney, indicating a highly selective transfer. CONCLUSIONS: NOS 3 cDNA transfer to cirrhotic rat liver is feasible and the increase in hepatic NOS 3 leads to a marked decrease in portal hypertension without systemic effects. These data indicate a major haemodynamic role of intrahepatic NOS 3 in the pathogenesis of portal hypertension in CCl(4) cirrhosis. 相似文献
10.
Abraldes JG Rodríguez-Vilarrupla A Graupera M Zafra C García-Calderó H García-Pagán JC Bosch J 《Journal of hepatology》2007,46(6):1040-1046
BACKGROUND/AIMS: Sinusoidal endothelial dysfunction with decreased nitric oxide (NO) production contributes to increased hepatic resistance in cirrhosis. Statins improve endothelial dysfunction in peripheral vasculature. This study was designed to characterize the hemodynamic and molecular effects of statins in cirrhotic rats. METHODS: Systemic and splanchnic hemodynamics were evaluated in CCl(4) ascitic cirrhotic rats treated with placebo or simvastatin (25 mg/kg/day, for 3 days), at baseline and after volume expansion. Vascular responses of liver vasculature were evaluated after isolation and perfusion of the liver. RESULTS: There were no differences in baseline hemodynamics in rats treated with simvastatin or placebo. However, in rats treated with simvastatin the increase in portal pressure induced by volume expansion was significantly attenuated. In isolated and perfused cirrhotic livers simvastatin pre-treatment significantly attenuated the pressure response to methoxamine, and significantly improved paradoxical vasoconstriction induced by acetylcholine. These effects were not observed in the presence of a nitric oxide synthase inhibitor. Simvastatin increased eNOS expression, Akt-dependent eNOS phosphorylation and cGMP liver content. CONCLUSIONS: The administration of simvastatin might constitute a new way to selectively increase NO availability in the cirrhotic liver circulation and, therefore improve the vascular disturbances that contribute to portal hypertension. 相似文献
11.
Gracia-Sancho J Laviña B Rodríguez-Vilarrupla A García-Calderó H Bosch J García-Pagán JC 《Journal of hepatology》2007,47(2):220-227
BACKGROUND/AIMS: Cyclooxygenase-1 (COX-1) is overexpressed in sinusoidal endothelial cells (SEC) of cirrhotic rat livers, and through an enhanced production of vasoconstrictor prostanoids contributes to increase intrahepatic resistance. Our study was aimed at investigating the role of enhanced AA bioavailability modulating the hepatic vascular tone of cirrhotic livers and identifying which prostanoid is involved. METHODS: SEC isolated from control and cirrhotic rat livers were incubated with AA, methoxamine or vehicle. TXA(2) was quantified. In addition, portal perfusion pressure (PP) response curves to AA were performed in rat livers pre-incubated with vehicle, SC-560 (COX-1 inhibitor), Furegrelate (inhibitor of TXA(2) synthesis) and SQ-29548 (PGH(2)/TXA(2) receptor blocker). cPLA2 activity was determined in control and cirrhotic livers. RESULTS: AA and methoxamine incubation promoted a significant increase in TXA(2) release by Cirrhotic-SEC, but not in Control-SEC. AA produced a dose-dependent increase in the PP, associated with increased TXA(2) release. These responses were significantly greater in cirrhotic livers. COX-1 inhibition and PGH(2)/TXA(2) receptor blockade, but not TXA(2) synthase inhibition, markedly attenuated the PP response to AA of cirrhotic livers. Additionally, cirrhotic livers exhibited significantly increased cPLA2 activity. CONCLUSIONS: An enhanced production of vasoconstrictor prostanoids, probably PGH(2), by SEC contributes to increase vascular tone of cirrhotic livers. 相似文献
12.
The role of nitric oxide in the reduction of protein kinase C-induced contractile response in aortae from rats with portal hypertension 总被引:1,自引:0,他引:1
Chagneau C Tazi KA Heller J Sogni P Poirel O Moreau R Lebrec D 《Journal of hepatology》2000,33(1):26-32
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. 相似文献
13.
Effects of Nitric Oxide Inhibition by Methylene Blue in Cirrhotic Patients with Ascites 总被引:2,自引:0,他引:2
Kalambokis G Economou M Fotopoulos A Bokharhii JA Christos P Paraskevi K Konstantinos P Katsaraki A Tsianos EV 《Digestive diseases and sciences》2005,50(10):1771-1777
Increased endogenous nitric oxide production has been proposed as an important mediator of the peripheral arterial vasodilation
and the hyperdynamic circulation in cirrhosis, whereas a decreased intrahepatic production of nitric oxide has been implicated
in the pathogenesis of portal hypertension. The present study investigated the possible beneficial effects of methylene blue,
which is a potent inhibitor of guanylate cyclase and nitric oxide synthase, on hyperdynamic circulation and renal function
in cirrhotic patients with ascites together with the effects on portal hemodynamics. Twenty patients were evaluated at baseline
and during 2 consecutive 4-hr periods after the administration of methylene blue at a dose of 3 mg/kg (10 patients) or placebo
(10 patients). Mean arterial pressure, heart rate, cardiac output, systemic vascular resistance, plasma active renin, plasma
aldosterone, plasma antidiuretic hormone, serum urea, serum creatinine, serum sodium, urinary flow rate, glomerular filtration
rate, effective renal plasma flow, portal flow volume, and portal vein velocity were not modified by methylene blue or placebo.
Urinary sodium excretion, fractional sodium excretion and serum nitric oxide levels were significantly decreased 4 hr after
methylene blue administration (P < 0.05), to return toward basal levels over a further 4-hr period. It is concluded that methylene blue, at the dose used
in the present study, has no effect on systemic and portal hemodynamics in cirrhotic patients with ascites. The reduction
in renal sodium excretion, in the absence of changes in renal function and hemodynamics, suggests, at least partly, a direct
antinatriuretic effect of methylene blue. 相似文献
14.
Pereira-Filho G Ferreira C Schwengber A Marroni C Zettler C Marroni N 《Arquivos de gastroenterologia》2008,45(2):156-162
BACKGROUND: Hepatic cirrhosis is the final stage of liver dysfunction, characterized by diffuse fibrosis which is the main response to the liver injury. The inhalatory carbon tetrachloride is an effective experimental model that triggers cirrhosis and allows to obtain histological and physiological modifications similar to the one seen in humans. AIM: To investigate the effects of N-acetylcysteine (NAC) on the fibrosis and oxidative stress in the liver of cirrhotic rats, analyzing liver function tests, lipoperoxidation, activity of glutathione peroxidase enzyme, collagen quantification, histopathology, as well as the nitric oxide role. METHODS: The animals were randomly in three experimental groups: control (CO); cirrhotic (CCl4) and CCl4 + NAC. Evaluate the lipid peroxidation, the glutathione peroxidase enzyme, the collagen and the expression of inducible nitric oxide synthase (iNOS). RESULTS: The cirrhotic group treated with N-acetylcysteine showed trough the histological analysis and collagen quantification lower degrees of fibrosis. This group has also shown less damage to the cellular membranes, less decrease on the glutathione peroxidase levels and less expression of inducible nitric oxide synthase when matched with the cirrhotic group without treatment. CONCLUSION: N-acetylcysteine seams to offer protection against hepatic fibrosis and oxidative stress in cirrhotic rat livers. 相似文献
15.
Lipoic acid prevents development of the hyperdynamic circulation in anesthetized rats with biliary cirrhosis 总被引:3,自引:0,他引:3
Marley R Holt S Fernando B Harry D Anand R Goodier D Davies S Moore K 《Hepatology (Baltimore, Md.)》1999,29(5):1358-1363
Chronic bile duct ligation is associated with the development of oxidant injury, biliary cirrhosis, portal hypertension, and a hyperdynamic circulation. We have previously demonstrated that the hyperdynamic circulation in the partial portal vein-ligated rat can be prevented by the administration of N-acetylcysteine. To extend these findings, we have examined the effect of lipoic acid, a thiol-containing antioxidant, on hemodynamics, oxidative stress, and nitric oxide (NO) production in bile duct-ligated (BDL) cirrhotic rats. Lipoic acid was given continuously in drinking water to normal and BDL rats; control rats received ordinary drinking water, and animals were studied at 24 days following surgery. Lipoic acid prevented the development of the hyperdynamic circulation (cardiac index [CI]: 15.7 +/- 2.0 vs. 29.5 +/- 2.1 mL x min-1 x 100 g-1; P <. 05) and significantly attenuated the rise in portal pressure (PP) (12.7 +/- 0.8 vs. 15.2 +/- 0.5 mm Hg; P <.05). Hepatic nitric oxide synthase (NOS) activity and plasma nitrite/nitrate concentration increased significantly following bile duct ligation, and both of these were prevented by lipoic acid. Lipoic acid had no effect on the biochemical or histological parameters of liver function in the cirrhotic group. We conclude that lipoic acid prevents the development of the hyperdynamic circulation in the rat model of biliary cirrhosis, and that this is associated with decreased synthesis of NO. 相似文献
16.
Cyclooxygenase-1 inhibition corrects endothelial dysfunction in cirrhotic rat livers 总被引:1,自引:0,他引:1
Graupera M García-Pagán JC Parés M Abraldes JG Roselló J Bosch J Rodés J 《Journal of hepatology》2003,39(4):515-521
BACKGROUND/AIMS: Cirrhotic livers exhibit endothelial dysfunction that contributes to the increased hepatic vascular resistance. The present study evaluates the role of cyclooxygenase (COX)-derived prostanoids, implicated in the pathogenesis of endothelial dysfunction in other settings, in the pathogenesis of endothelial dysfunction in cirrhotic livers. METHODS: Endothelial dysfunction was evaluated by performing concentration-effect curves to acetylcholine after precontracting the liver with methoxamine in groups of control and CCl(4)-cirrhotic rat livers preincubated either with vehicle, indomethacin, the COX-1 selective inhibitor, SC-560, the COX-2 selective inhibitor, SC-236, the thromboxane A(2) receptor antagonist, SQ 29,548 or the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine. Thromboxane A(2) (TXA(2)) production was determined in samples of the perfusate. RESULTS: Cirrhotic livers exhibited endothelial dysfunction, as shown by the significantly lower relaxation to acetylcholine than control livers, that was totally corrected by indomethacin. COX-1 inhibition and TXA(2) blockade, but not COX-2 inhibition, also corrected endothelial dysfunction. Acetylcholine significantly increased TXA(2) production in cirrhotic but not in control livers. Indomethacin and COX-1 inhibition, but not COX-2 or NO inhibition, prevented the increased production of TXA(2). CONCLUSIONS: An increased production of TXA(2) is involved in the pathogenesis of endothelial dysfunction in cirrhotic rat livers. This is mainly mediated by COX-1, but not by COX-2. 相似文献
17.
BACKGROUND/AIMS: Increased intrahepatic vascular tone can be pharmacologically manipulated in isolated cirrhotic livers. Intrahepatic endothelial dysfunction may lead to a decreased production of the potent endogenous vasodilator nitric oxide in cirrhotic livers. The aims of the study were to determine whether portal pressure can be lowered in vivo by injecting nitric oxide donors glyceryl trinitrate or nitroprusside directly in the portal vein and whether this is related to a decrease in intrahepatic resistance. METHODS: In anaesthetised CCl4 cirrhotic rats, intraportal doses of glyceryl trinitrate 0.5, 1 or 5 microg/kg/ min or nitroprusside 1, 5 or 10 microg/kg/min did not decrease portal pressure but only arterial pressure. Systemic and splanchnic haemodynamics were measured before and during 15 min intraportal infusion of glyceryl trinitrate 10 microg/kg/min or nitroprusside 20 microg/kg/min. RESULTS: Glyceryl trinitrate decreased portal pressure from 14.0+/-1.1 to 11.8+/-1.4 mm Hg, splanchnic perfusion pressure from 102+/-10 to 74+/-5 mm Hg and portal sinusoidal flow from 2.11+/-0.38 to 1.70+/-0.35 ml/min/g liver (all p<0.05). Nitroprusside did not decrease portal pressure significantly but led to a reduction of the splanchnic perfusion pressure (104+/-9 to 66+/-7 mm Hg) and the portal sinusoidal flow (2.39+/-0.50 to 1.77+/-0.31 ml/min/g liver; all p<0.05). Portal sinusoidal resistance was not altered by either drug. CONCLUSIONS: Intraportal infusion of nitric oxide donors decreased arterial pressure more than portal pressure. Portal sinusoidal resistance remained unaffected, but the liver parenchyma became less perfused with high doses. The systemic effects of nitric oxide donating drugs prevailed. 相似文献
18.
5-lipoxygenase inhibition reduces intrahepatic vascular resistance of cirrhotic rat livers: a possible role of cysteinyl-leukotrienes 总被引:7,自引:0,他引:7
Graupera M García-Pagán JC Titos E Claria J Massaguer A Bosch J Rodés J 《Gastroenterology》2002,122(2):387-393
BACKGROUND & AIMS: Cysteinyl-leukotrienes (Cys-LTs) increase intrahepatic vascular resistance in normal rat livers. CCl4 cirrhotic rat livers have increased Cys-LT production and 5-lipoxygenase messenger RNA (mRNA) expression. The aim of this study was to investigate the role of 5-lipoxygenase-derived eicosanoids regulating intrahepatic vascular tone in control and CCl4-induced cirrhotic rat livers. METHODS: In different groups of portally perfused control and cirrhotic rat livers, the following were analyzed: a portal perfusion pressure (PP) dose-response curve to LTD4; the effects on PP caused by either vehicle, the selective 5-lipoxygenase inhibitor AA-861, the selective Cys-LT1 receptor antagonist MK-571, or the dual Cys-LT1 and Cys-LT2 receptor antagonist BAY u9773; and immunohistochemistry for 5-lipoxygenase in liver sections of cirrhotic and control livers. RESULTS: Cirrhotic livers have a hyperesponse to LTD4. In control livers, AA-861 and MK-571 produced a moderate and similar reduction in PP. In cirrhotic livers, 5-lipoxygenase inhibition produced a marked and significantly greater reduction in PP than in controls. However, no effect on PP was observed after MK-571 or BAY u9773. 5-Lipoxygenase-positive cells were markedly increased in cirrhotic livers. CONCLUSIONS: Our results suggest that 5-lipoxygenase-derived eicosanoids may contribute to the increased intrahepatic vascular resistance of cirrhotic rat livers and therefore the pathogenesis of portal hypertension. 相似文献
19.
Aims/hypothesis
Cytokines stimulate nitric oxide production in pancreatic beta cells, leading to endoplasmic reticulum (ER) stress and apoptosis. Treatment of beta cells with glucose and NEFA induces nitric oxide synthase (NOS) as well as ER stress. However, the role of NO in glucolipotoxicity-induced ER stress in beta cells is not clear. 相似文献20.
Zhang HY Han de W Su AR Zhang LT Zhao ZF Ji JQ Li BH Ji C 《World journal of gastroenterology : WJG》2007,13(47):6385-6395
AIM: To characterize the correlation between severity of hepatopulmonary syndrome (HPS) and degree of hepatic dysfunction, and to explore how intestinal endotoxemia (IETM) affects the development of HPS in cirrhotic rats.
METHODS: Male Wister rats were fed with a diet containing maize flour, lard, cholesterol, and alcohol and injected subcutaneously with CCl4 oil solution every two days for 8 wk to induce typical cirrhosis and development of HPS. The animals were also given a nitric oxide (NO) production inhibitor, N^ω-nitro-L-arginine methyl ester (L-NAME) intraperitoneally, and an iNOS inhibitor, aminoguanidine hydrochloride (AG) via gavage daily from the end of the 4th wk to the end of the 6th or 8th wk, or a HO-1 inhibitor, zinc protoporphyrin (ZnPP) intraperitoneally 12 h prior to killing. Blood, liver and lung tissues were sampled.
RESULTS: Histological deterioration of the lung paralleled to that of the liver in the cirrhotic rats. The number of pulmonary capillaries was progressively increased from 6.1 ± 1.1 (count/filed) at the 4th wk to 14.5 ± 2.4 (count/filed) at the 8th wk in the cirrhotic rats. Increased pulmonary capillaries were associated with increased blood levels of lipopolysaccharide (LPS) (0.31 ± 0.08 EU/mL vs control 0.09 ± 0.03 EU/mL), alanine transferase (ALT, 219.1 ± 17.4 U/L vs control 5.9 ± 2.2 U/L) and portal vein pressure. Compared with normal control animals, the number of total cells in bronchoalveolar lavage fluid (BALF) of the cirrhotic rats at the 8th wk was not changed, but the number of macrophages and the ratio of macrophages to total cells were increased by nearly 2-fold, protein expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) started to increase significantly at the 4th wk, and reached its peak at the 8th wk in the lung of cirrhotic rats. The increase of iNOS expression appeared to be quicker than that of eNOS. NO2^-/NO3^- was also increased, which was cor 相似文献
METHODS: Male Wister rats were fed with a diet containing maize flour, lard, cholesterol, and alcohol and injected subcutaneously with CCl4 oil solution every two days for 8 wk to induce typical cirrhosis and development of HPS. The animals were also given a nitric oxide (NO) production inhibitor, N^ω-nitro-L-arginine methyl ester (L-NAME) intraperitoneally, and an iNOS inhibitor, aminoguanidine hydrochloride (AG) via gavage daily from the end of the 4th wk to the end of the 6th or 8th wk, or a HO-1 inhibitor, zinc protoporphyrin (ZnPP) intraperitoneally 12 h prior to killing. Blood, liver and lung tissues were sampled.
RESULTS: Histological deterioration of the lung paralleled to that of the liver in the cirrhotic rats. The number of pulmonary capillaries was progressively increased from 6.1 ± 1.1 (count/filed) at the 4th wk to 14.5 ± 2.4 (count/filed) at the 8th wk in the cirrhotic rats. Increased pulmonary capillaries were associated with increased blood levels of lipopolysaccharide (LPS) (0.31 ± 0.08 EU/mL vs control 0.09 ± 0.03 EU/mL), alanine transferase (ALT, 219.1 ± 17.4 U/L vs control 5.9 ± 2.2 U/L) and portal vein pressure. Compared with normal control animals, the number of total cells in bronchoalveolar lavage fluid (BALF) of the cirrhotic rats at the 8th wk was not changed, but the number of macrophages and the ratio of macrophages to total cells were increased by nearly 2-fold, protein expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) started to increase significantly at the 4th wk, and reached its peak at the 8th wk in the lung of cirrhotic rats. The increase of iNOS expression appeared to be quicker than that of eNOS. NO2^-/NO3^- was also increased, which was cor 相似文献