Metabolic and hemodynamic responses of bivascularly perfused rat liver to nerve stimulation, noradrenaline, acetylcholine and glucagon in thioacetamide-induced micronodular cirrhosis

Zimmermann, Thomas; Gardemann, Andreas; Machnik, G; Dargel, R.; Jungermann, Kurt

doi:10.1002/hep.1840150319

Cited by 21 publications

(5 citation statements)

References 35 publications

(19 reference statements)

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“…More recently, Rockey and Chung9 have reported a 75% decrease in cNOS activity by the citrulline assay in isolated sinusoidal endothelial cells from a rat model of carbon tetrachloride induced cirrhosis. Depletion of constitutively expressed NO in the cirrhotic liver is consistent with the finding that the intrahepatic portal vascular bed of the cirrhotic liver exhibits hyper-reactivity to vasoconstriction by noradrenaline20and to sympathetic nerve stimulation,21 in contrast to the hyporesponsiveness to vasoconstrictor agents known to occur in other regions of the peripheral vasculature in cirrhosis 222.…”

Section: Discussionsupporting

confidence: 82%

Hepatic and splanchnic nitric oxide activity in patients with cirrhosis

Sarela

Mihaimeed

Batten

et al. 1999

Gut

106

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Background-In animal models of cirrhosis, altered activity of nitric oxide (NO) has been implicated in the pathogenesis of increased intrahepatic portal vascular resistance and abnormal mesenteric vasodilatation. Aims-To investigate NO activity in the liver and splanchnic vascular bed of patients with cirrhosis. Methods-Activity of the calcium dependent constitutive and calcium independent inducible isoforms of NO synthase (cNOS and iNOS, respectively) was assayed biochemically in biopsy specimens of liver and a vascular portion of the greater omentum (representative of mesenteric vasculature) obtained from patients with cirrhosis undergoing liver transplantation (n=14) and non-cirrhotic control patients undergoing liver resection for metastases (n=9). The concentration of NO metabolites (NO 2 + NO 3 ) in portal and peripheral venous plasma was measured. Results-The activity of cNOS was lower in cirrhotic compared with non-cirrhotic subjects for both liver and omentum. Hepatic and omental iNOS activities did not diVer significantly between the two groups. Portal (NO 2 + NO 3 ) was threefold higher in cirrhotic than non-cirrhotic patients, but no diVerences were observed in systemic venous samples from the two groups. Conclusions-The activity of cNOS is diminished in the cirrhotic human liver. The resultant decrease in constitutive NO release may promote an increase in the intrahepatic portal vascular resistance. Elevated portal venous (NO 2 + NO 3 ) indicates enhanced splanchnic vascular release of NO in cirrhotic patients, but the absence of increased NOS activity in the mesenteric vasculature suggests diVerential regulation of NO synthesis within the splanchnic vascular bed. (Gut 1999;44:749-753)

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Section: Discussionsupporting

confidence: 82%

Hepatic and splanchnic nitric oxide activity in patients with cirrhosis

Sarela

Mihaimeed

Batten

et al. 1999

Gut

106

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“…We have studied a model for hepatic encephalopathy in mice with liver damage generated by bile duct ligation and TAA administration. TAA is a hepatotoxin that causes intrahepatic metabolic changes (40) and has often been used to induce cirrhosis in animals (41). Our previous studies have shown that cerebral dysfunction accompanies TAA-induced cirrhosis and may partly reflect the condition of hepatic encephalopathy (23).…”

Section: Discussionmentioning

confidence: 99%

Cannabinoids ameliorate cerebral dysfunction following liver failure via AMP‐activated protein kinase

Dagon¹,

Avraham²,

Ilan³

et al. 2007

FASEB j.

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Hepatic encephalopathy (HE) is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We studied the etiology of cerebral dysfunction in a murine model of HE induced by either bile duct ligation or thioacetamide administration. We report that stimulation of cerebral AMP-activated protein kinase (AMPK), a major intracellular energy sensor, is a compensatory response to liver failure. This function of AMPK is regulated by endocannabinoids. The cannabinoid system controls systemic energy balance via the cannabinoid receptors CB-1 and CB-2. Under normal circumstances, AMPK activity is mediated by CB-1 while CB-2 is barely detected. However, CB-2 is strongly stimulated in response to liver failure. Administration of delta9-tetrahydrocannabinol (THC) augmented AMPK activity and restored brain function in WT mice but not in their CB-2 KO littermates. These results suggest that HE is a disease of energy flux. CB-2 signaling is a cerebral stress response mechanism and makes AMPK a promising target for its treatment by modulating the cannabinoid system.

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“…Also, the reduced generation of the oxygen radical may have been caused by the lowered energy charge (37). On the other hand, alterations of the membrane structure reported in cirrhosis (38,39) may have affected the formation of the multimolecular oxidase complex. It is interesting to note that the lowered membrane fluidity in chemically-induced cirrhosis changed the activity of enzymes embedded in the membrane (39).…”

Section: Discussionmentioning

confidence: 99%

Oxygen radical formation, proliferative activity and phagocytic capacity of cultivated macrophages from cirrhotic rat livers

Vogl

Petermann

Dargel

1996

Liver

Self Cite

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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.

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Metabolic and hemodynamic responses of bivascularly perfused rat liver to nerve stimulation, noradrenaline, acetylcholine and glucagon in thioacetamide-induced micronodular cirrhosis

Cited by 21 publications

References 35 publications

Hepatic and splanchnic nitric oxide activity in patients with cirrhosis

Hepatic and splanchnic nitric oxide activity in patients with cirrhosis

Cannabinoids ameliorate cerebral dysfunction following liver failure via AMP‐activated protein kinase

Oxygen radical formation, proliferative activity and phagocytic capacity of cultivated macrophages from cirrhotic rat livers

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