Prevention of ischemia/reperfusion injury in the rat liver by atrial natriuretic peptide

Bilzer, Manfred; Witthaut, R; Paumgartner, Gustav; Gerbes, Alexander L.

doi:10.1016/s0016-5085(94)94961-1

Cited by 56 publications

(38 citation statements)

References 47 publications

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“…Persistently decreased bile flow also has been described in prolonged hepatic cold (24-hour) ischemia and warm (60-minute) ischemia in isolated perfused rat liver systems during the entire reperfusion period, which usually lasts120 minutes or less in liver perfusion systems. 8,10,[31][32][33] In the present study, using a 30-minute lobar ischemia, we were able to induce a milder form of cholestasis associated with a relatively small increase in serum ALT and AST and tissue MPO activities and minimal histological alterations. All these alterations were reversible within 3 days of reperfusion.…”

Section: Discussionmentioning

confidence: 95%

“…[8][9][10] This is relevant because in addition to the antioxidant properties of GSH, its excretion into bile represents a significant osmotic driving force of bile salt-independent flow, 28 accounting for approximately half the total bile flow rate in rats. 7 Thus, impaired biliary GSH excretion may explain the reduction in bile flow observed in ILs during the reperfusion period.…”

Section: Discussionmentioning

confidence: 99%

“…Studies performed in isolated perfused rat livers using bile acid-free perfusion buffer have shown that a significant proportion of bile salt-independent bile flow is not dependent on GSH excretion in control livers or postischemic livers. 8,9 Therefore, it is likely that excretion of other molecules that contribute to this fraction of bile flow 7 is unaffected or even increased after I-R injury, maintaining bile flow within control limits despite the marked decrease in GSH excretion observed in NILs and also ILs at 7-day reperfusion.…”

Section: Discussionmentioning

confidence: 99%

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Bile secretory function after warm hepatic ischemia-reperfusion injury in the rat

Accatino¹,

Pizarro²,

Solı́s³

et al. 2003

Liver Transplantation

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Hepatic ischemia-reperfusion (I-R) injury frequently is associated with cholestasis. However, the underlying mechanisms are not fully understood. The aim of the study is to assess bile secretory function in vivo in rats subjected to warm lobar hepatic ischemia at different times during reperfusion. A model of lobar 70% warm hepatic ischemia for 30 minutes was used with studies conducted at 1 and 6 hours and 1, 3, and 7 days after reperfusion. Bile secretory function was assessed after selective cannulation of bile ducts of ischemic (ILs) and nonischemic lobes (NILs). Serum activity of hepatic alanine and aspartate aminotransferase was slightly increased in rats subjected to I-R, whereas serum bile salt levels increased early during reperfusion, returning to control values after 7 days. ILs showed mild reversible leukocyte infiltration and no significant necrosis. Bile flow and bile salt excretion were significantly decreased in ILs during the first 24-hour reperfusion period compared with shamoperated rats and NILs. A marked reduction in glutathione (GSH) excretion occurred at 1 and 6 hours and 1 and 3 days, which returned to control values after 7 days. Total GSH and both reduced and oxidized GSH levels in liver homogenate and arterial blood GSH levels were unchanged at all times. Protein mass of multidrug resistance protein 2 and its function, assessed by the hepatic maximum secretory rate of ceftriaxone, did not show significant changes in ILs or NILs compared with shamoperated rats. Liver tissue ␥-glutamyl transpeptidase (GGT) and ␥-glutamylcysteine synthetase activities remained unchanged, whereas biliary GGT and cysteine secretory rates were significantly increased in ILs and NILs. Administration of acivicin, a GGT inhibitor, resulted in decreased secretion of this enzyme into bile and a parallel marked increase in biliary GSH secretion compared with untreated ischemic rats. In conclusion, warm hepatic I-R induces reversible cholestatic changes in ILs. GSH secretory rates from both ILs and NILs were markedly decreased during reperfusion. The reversibility of this effect after GGT inhibition, as well as increased release of active GGT into bile and cysteine biliary secretory rates, suggest increased GSH degradation in bile. These findings might be relevant for the I-R-induced clinical cholestasis, as well as cholangiocyte injury, seen after hepatic ischemia. (Liver Transpl 2003;9:1199-1210.)

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Bile secretory function after warm hepatic ischemia-reperfusion injury in the rat

Accatino¹,

Pizarro²,

Solı́s³

et al. 2003

Liver Transplantation

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“…Thereafter, the perfusion flow was turned off for 60 min to produce warm ischemia (30°C). During ischemia the livers were covered with wet gaze to avoid drying [33]. The temperature during ischemia was kept constant by means of a heating lamp.…”

Section: Methodsmentioning

confidence: 99%

“…The effect of GSH on reperfusion injury was studied in isolated perfused rat livers subjected to 1 h of warm ischemia. The release of lactate dehydrogenase (LDH), as well as bile flow, were determined as parameters of cell damage and of liver function, respectively [33, 34]. In a second set of experiments, we investigated the effect of GSH treatment on cell injury following KC activation in perfused rat livers.…”

Section: Introductionmentioning

confidence: 99%

Glutathione Treatment Protects the Rat Liver against Injury after Warm Ischemia and Kupffer Cell Activation

Bilzer¹,

Baron²,

Schauer

et al. 2002

Digestion

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Background/Aim: The generation of reactive oxygen species by activated Kupffer cells (KC) may contribute to reperfusion injury of the liver during liver transplantation or resection. The aim of our present studies was to investigate (1) prevention of hepatic reperfusion injury after warm ischemia by administration of the antioxidant glutathione (GSH) and (2) whether GSH confers protection through influences on KC toxicity. Methods: Isolated perfused rat livers were subjected to 1 h of warm ischemia followed by 90 min of reperfusion without (n = 5) or with GSH or catalase (n = 4–5 each). Selective KC activation by zymosan (150 µg/ml) in continuously perfused rat livers was used to investigate KC-related liver injury. Results: Postischemic infusion of 0.1, 0.5, 1.0 and 2.0 mM GSH, but not 0.05 mM GSH prevented reperfusion injury after warm ischemia as indicated by a marked reduction of sinusoidal LDH efflux by up to 83 ± 13% (mean ± SD; p < 0.05) and a concomitant significant improvement of postischemic bile flow by 58 ± 27% (p < 0.05). A similar protection was conveyed by KC blockade with gadolinium chloride indicating prevention of KC-related reperfusion injury by postischemic GSH treatment. Postischemic treatment with catalase (150 U/ml) resulted in a reduction of LDH efflux by 40 ± 9% (p < 0.05). Accordingly, catalase as well as GSH (0.1–2.0 mM) nearly completely prevented the increase in LDH efflux following selective KC activation by zymosan in continously perfused rat livers. Conclusion: Postischemic administration of GSH protects the liver against reperfusion injury after warm ischemia. Detoxification of KC-derived hydrogen peroxide seem to be an important feature of the protective mechanisms.

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The Guanylate Cyclase-Coupled Natriuretic Peptide Receptor: A New Target for Prevention of Cold Ischemia-Reperfusion Damage of the Rat Liver

Gerbes¹,

Vollmar

Kiemer

et al. 1998

Hepatology

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The aim of our studies was to investigate hormonal prevention of hepatic preservation damage by the atrial natriuretic peptide (ANP) and the mechanisms involved. Isolated perfusion of rat livers was performed in a nonrecirculating fashion. Twenty minutes of preischemic perfusion was performed with or without different concentrations of ANP, followed by 24-hour storage in cold University of Wisconsin (UW) solution. Two hundred nanomoles of ANP prevented hepatocellular damage during a 2-hour reperfusion period as indicated by a marked attenuation of the sinusoidal efflux of lactate dehydrogenase (LDH) and purine nucleoside phosphorylase (PNP), and by reduced Trypan blue uptake. Ischemia-reperfusion injury (IRPI) of the liver is a major clinical problem after liver transplantation. Preservation injury of the graft liver has been reduced by the introduction of the University of Wisconsin (UW) solution. 1 Still, severe problems such as primary nonfunction, dysfunction, and nonanastomotic biliary stenosis after liver transplantation are mainly caused by ischemia-reperfusion damage of the graft. 2,3 Moreover, improved organ preservation might increase the number of liver transplants that is limited by the lack of donor organs. At present, only about two thirds of organs offered for transplantation are accepted, 4 and fatty livers or organs of donors with prolonged intensive care are rejected. In these organs, primary nonfunction is more frequent, and graft as well as patient survival is diminished. 5,6 This is also a result of increased vulnerability upon ischemia-reperfusion damage. Thus, IRPI is pivotal for morbidity and mortality after liver transplantation. Therefore, better protection against ischemia-reperfusion damage is urgently needed.A variety of mechanisms are important for cold IRPI of the liver. Lack of oxygen during ischemia induces depletion of adenosine triphosphate (ATP), followed by a deterioration of the intracellular Ca 2ϩ and Na ϩ homeostasis and the activation of cytotoxic enzymes such as proteases, phospholipases, and endonucleases. 7-10 During reperfusion, sinusoidal oxidative stress, e.g., by Kupffer cells and neutrophils, seems to play an important role. 11-13 Furthermore, the activation of these cells induces a complex network of cytokines accompanied by vascular inflammation. 14-16 Nuclear factor B (NF-B) plays a pivotal role in the complex relation of these pathophysiological events. [17][18][19][20] The incomplete understanding of IRPI may explain the lack of established pharmacological prevention. We have recently shown that the rat liver can be protected from damage after warm ischemia by treatment with atrial natriuretic peptide (ANP). 21 This circulating hormone released by the heart in response to volume expansion or cardiac hypoxia has received attention mainly for its vasodilating properties. [22][23][24][25] However, recent evidence shows an impact of ANP on other biological functions, e.g., of the immune system. 26,27 In this respect, an influence of ANP on macrophage activation h...

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Prevention of ischemia/reperfusion injury in the rat liver by atrial natriuretic peptide

Cited by 56 publications

References 47 publications

Bile secretory function after warm hepatic ischemia-reperfusion injury in the rat

Bile secretory function after warm hepatic ischemia-reperfusion injury in the rat

Glutathione Treatment Protects the Rat Liver against Injury after Warm Ischemia and Kupffer Cell Activation

The Guanylate Cyclase-Coupled Natriuretic Peptide Receptor: A New Target for Prevention of Cold Ischemia-Reperfusion Damage of the Rat Liver

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