Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0008370 (cholestasis)
 9,378 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of furosemide on hepatic bile formation was studied in isolated perfused rat liver to determine if 1) the observed cholestatic effect at lower dose of furosemide in vivo is a primary effect or a secondary effect due to decreased hepatic blood flow caused by the furosemide-induced volume contraction and if 2) the observed choleretic effect at higher doses can be explained by the osmotic effect of furosemide and its metabolites in bile. A single dose of furosemide (initial perfusate concentration 0.01, 0.1 or 1 mM) produced choleresis, whereas 0.001 mM furosemide did not affect bile flow significantly. Because furosemide failed to produce cholestasis at tested doses, the observed cholestasis in vivo at similar blood concentrations must be a secondary effect. Furosemide choleresis was associated with biliary secretion of furosemide and its metabolites. However, the choleretic effect expressed as microliters per micromole of drug secreted declined with increasing dose and biliary secretion. Furosemide choleresis was also associated with an increase in the net biliary secretion of Na+ and Cl-. The effect of Na+ and Cl- replacement on furosemide choleresis was studied to determine if the choleresis was a result of direct effect of furosemide on hepatic electrolyte transport. Replacement of perfusate Na+ completely by Li+ or partially by choline+ resulted in a 30 to 50% reduction in choleretic effect and furosemide-induced biliary Cl- secretion. A similar decline in choleretic effect and net furosemide-induced biliary Na+ secretion was also observed when perfusate Cl- was replaced by nitrate, acetate or isethionate.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Furosemide choleresis in isolated perfused rat liver: partial dependency on perfusate sodium and chloride. 299 29

The effect of local anesthetics, dibucaine and procaine, on hepatic bile formation was studied in the isolated perfused rat liver. Perfusate Na+ and Cl- were replaced by other ions to define the possible mechanism of action. A single dose (50 mumol) of dibucaine produced an initial cholestasis followed by choleresis. Whereas dibucaine produced only choleresis at a lower dose (10 mumol), only the cholestatic effect was seen at a higher dose (100 mumol). Procaine, on the other hand, produced only choleresis at all doses (1, 10 and 100 mumol); this choleresis was associated with biliary secretion of procaine and its metabolites. Neither dibucaine nor procaine affected the low endogenous bile acid secretion in these studies. The diffusion permeability coefficient of [carboxy-14C]inulin was not altered significantly by dibucaine and procaine, suggesting no significant alteration of biliary permeability. Biliary secretion of Na+ or Cl- declined during cholestasis and increased during choleresis. The initial cholestatic effect of dibucaine was still present when perfusates Na+ and Cl- were replaced by permeable Li+ or NO3-, but declined when Cl- was replaced by relatively impermeable isethionate, suggesting a nonspecific effect. The choleretic effect of both dibucaine and procaine, however, declined significantly when Na+ or Cl- was replaced by Li+, NO3- or isethionate-. These ion-substitutions did not affect significantly the biliary secretion of procaine and its metabolites. The ability to induce biliary secretion of Na+ and Cl- also decreased when Cl- was replaced by NO3- or isethionate and when Na+ was replaced by Li+, respectively. These results suggest that a part of the choleretic effect of both dibucaine and procaine is specifically dependent on Na+ and Cl-. This fraction is thus unlikely to be due to the osmotic effect of the secreted drug. Further studies showed that dibucaine inhibited Na+-dependent hepatic uptake of taurocholate, suggesting possible interference with other Na+-dependent transport processes. It is proposed that although a part of the choleresis is due to the osmotic effect of the secreted drug, the specific dependency of a portion of the choleretic effect on Na+ and Cl- is due to inhibition of Na+-coupled Cl- reabsorption from the canaliculi.
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PMID:Sodium and chloride dependency of dibucaine- and procaine-induced choleresis in isolated perfused rat livers. 684 92

Cholestasis in patients with sepsis has been attributed to the effects of endotoxin (lipopolysaccharides, LPS) and LPS-induced cytokines, which are also potent stimulators of systemic and hepatic nitric oxide (NO) synthesis. NO donors stimulate bile acid-independent bile flow in normal rat liver, but the effects of LPS-induced NO on bile formation remain unclear. To address this question we examined the effects of NO and its mediator guanosine 3',5'-cyclic monophosphate (cGMP) on bile flow and biliary HCO3- and glutathione excretion in isolated perfused rat livers (IPRL) from LPS-treated rats. Portal and systemic NO2- + NO3- plasma levels were increased 47-fold in LPS-treated rats and were also elevated in perfusate (6-fold) and bile (9-fold) after isolating and perfusing livers from these animals. Bile flow, HCO3-, and glutathione output were decreased by 33%, 25%, and 81% in these IPRL, respectively. Stimulation of NO synthesis with L-arginine or inhibition of inducible NO synthesis with aminoguanidine did not change bile flow, although pretreatment with aminoguanidine inhibited NO production by 85%. Moreover, the choleretic effects of infusions of the NO donors sodium nitroprusside (SNP) and S-nitroso-acetyl-penicillamine were markedly reduced in endotoxemic IPRL compared with normal controls, and SNP-induced HCO3- and glutathione excretion were reduced by 61% and 86%, respectively. SNP-induced cyclic GMP production was 2.3-fold lower than in normals, but the choleretic effect of dibutyryl cGMP was only slightly reduced in endotoxemic livers. These findings indicate that LPS reduces bile acid-independent bile flow primarily by inhibiting biliary excretion of glutathione and to a lesser extent HCO3-, whereas LPS-induced NO does not modulate bile formation in endotoxemia. Thus, impairment of the major determinants of bile acid-independent bile flow by LPS may contribute significantly to the pathogenesis of the cholestasis of sepsis.
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PMID:Endotoxin impairs biliary glutathione and HCO3- excretion and blocks the choleretic effect of nitric oxide in rat liver. 914 37

Hepatic blood flow decreases under cholestasis and there is evidence that NO regulates liver microvascular perfusion. Thus, the aim of the present study was to evaluate NO synthesis in cholestasis. Cholestasis was induced by bile-duct ligation (BDL) in male Wistar rats. Bilirubins and enzyme activities were measured in serum. Lipid peroxidation, GSH, GSSG and glycogen were determined in liver. Histopathological analysis was performed. Serum NO2- + NO3- concentration was measured by the Gries reaction. iNOS immunoblot analysis was carried out using an iNOS polyclonal antibody. After 7 days of BDL lipid peroxidation increased while GSH/GSSG ratio decreased. Serum NO2- + NO3- and liver iNOS protein were reduced, accompanied by ischemia as revealed by the histopathological analysis. GSH upregulates NO synthesis by increasing iNOS mRNA levels and iNOS activity, thus the reduction of GSH/GSSG ratio may be responsible for the downregulation of iNOS protein and NO synthesis, which in turn may explain the observed ischemia and the decreased hepatic blood perfusion in cholestasis reported by others.
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PMID:Nitric oxide and inducible nitric oxide synthase expression are downregulated in acute cholestasis in the rat accompanied by liver ischemia. 1124 95

Interaction between endogenous opioids and nitric oxide (NO) has been shown in different biological models and pharmacological evidence suggest that opioids can induce NO release in endothelium as well as in neural cells. Cholestasis is associated with NO overproduction. The reason for increased NO synthesis is not clearly known but it can potentiate development of gastric mucosal damage in cholestatic subjects. Based on increased plasma levels of endogenous opioids and existence of NO overproduction in cholestasis, the present experiments were performed to investigate the role of interaction between endogenous opioids and NO in generation of ethanol-induced gastric damage in cholestatic rats. Cholestasis was induced by surgical ligation of bile duct and sham-operated rats served as controls. The animals received either 20 mg/kg of naltrexone or saline for 6 days and then were fasted and received L-arginine (200 mg/kg), NG-nitro-L-arginine methylester (L-NAME; 2, 5 and 10 mg/kg) or saline. The ethanol-induced gastric mucosal damage was significantly more severe in cholestatic rats than in sham-operated animals (115 +/- 12 mm2 vs. 72 +/- 11 mm2, P < 0.05). L-NAME significantly enhanced the development of gastric mucosal lesions in sham-operated rats. But in cholestatic animals, L-NAME decreased and L-arginine enhanced the severity of gastric damage. Pretreatment of animals with naltrexone decreased severity of gastric mucosal damage in cholestatic rats. Concurrent administration of naltrexone with L-arginine was protective against ethanol-induced gastric damage in both normal and cholestatic groups. Administration of naltrexone with L-NAME had the same effect in cholestatic and control rats and increased severity of gastric damage. Plasma levels of NO2- + NO3- were significantly higher in cholestatic rats than control animals (72 +/- 6 microM vs. 39 +/- 3 microM, P < 0.05). Pretreatment of animals with naltrexone significantly reduced plasma levels of NO2- + NO3- in cholestatic animals, but not in control rats (33 +/- 6 microM vs. 32 +/- 4 microM). The protective effect of L-NAME against gastric damage in cholestatic rats can be explained by inhibition of NO overproduction and it seems that interaction between opioids and NO may have an important role in generation of NO overproduction and gastric complications in cholestatic rats.
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PMID:The role of the interaction between endogenous opioids and nitric oxide in the pathophysiology of ethanol-induced gastric damage in cholestatic rats. 1146 29

1. Cholestatic liver disease is associated with nitric oxide (NO) overproduction and bradycardia. Nitric oxide has a dual effect on sinoatrial node and its effects depend on its concentration. Nitric oxide can increase heart rate by activating hyperpolarization-activated pacemaker current (If) but, at high concentrations, it can potentially decrease heart rate by inhibition of L-type calcium current. In the present study, the responsiveness of isolated atria to CsCl (an inhibitor of the If current) and acetylcholine (ACh; which decreases L-type calcium current through a NO-dependent pathway) were evaluated in bile duct-ligated and sham-operated control rats. 2. Bile duct ligation induced a significant decrease in the negative chronotropic effect of CsCl (0.2-5 mmol/L), but increased the responsiveness of isolated atria to ACh (10-8 to 10-3 mol/L). These effects were restored after incubation of the atria in the presence of the NO synthase inhibitor NG-nitro-l-arginine methyl ester (0.1 mmol/L). 3. Anaesthetized bile duct-ligated rats showed bradycardia and the plasma levels of NO2-/NO3- were significantly higher in bile duct-ligated rats compared with sham-operated animals. 4. Different and opposite responses of atria of cholestatic rats to CsCl and ACh can be explained by NO overproduction in bile duct-ligated animals. A dual role of NO in the regulation of the sinoatrial node may be responsible for this opposite effect and may have a role in the pathophysiology of cholestasis-induced bradycardia.
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PMID:Dual nitric oxide mechanisms of cholestasis-induced bradycardia in the rat. 1220 70

A variety of hepatobiliary abnormalities occur in inflammatory bowel diseases (IBDs). The role of tight junction (TJ) in hepatobiliary complications have been well described. The purpose of this study was to investigate the role of inducible nitric oxide (NOS) in alteration of hepatocyte TJ paracellular barrier and in the rapid transcytotic vesicular pathway modification associated with intestinal inflammation. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). When compared to DNBS-treated iNOS wild-type (WT) mice, DNBS-treated iNOS knock out mice (iNOSKO) mice experienced a significant less rate of the extent and severity of the histological signs of colon injury. Colon levels of the pro-inflammatory cytokines tumour necrosis factor, interleukin-1beta and interleukin-6 were also significantly reduced in iNOS-KO mice in comparison to wild-type mice. Liver histology from iNOSKO and wild-type mice iNOSWT did not show any parenchymal and portal tract inflammation at 4 days after DNBS administration. Serum total bilirubin and alanine aminotransferase, were significantly reduced in DNBS-iNOSKO mice vs DNBS-iNOSKO mice. Therefore, we found an increase of tight junctional permeability to lanthanum nitrate (molecular weight, 433) in the livers from DNBS-treated IL-10WT mice, lanthanum accumulated throughout the junctional area up to the most apical region bordering the lumen. Absence of a functional iNOS gene in iNOSKO mice resulted in a significant reduction of apical diffusion of lanthanum after DNBS-induced colitis. Immunofluorescent labeling of frozen liver sections from DNBS-iNOSWT mice showed a significant alteration of the immunolocalization for claudin-1 and zonula occludens (ZO)-1. In contrast, a significant reduced alteration in the localization of the immunosignals for claudin-1 and ZO-1 was observed in the liver from iNOSKO mice after DNBS administration. In conclusion, we suggest that the iNOS may represent an important pathophysiological mechanism of hepatobiliary injuries and cholestasis observed in patients with IBD.
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PMID:Role of iNOS in hepatocyte tight junction alteration in mouse model of experimental colitis. 1283 36

Endotoxin-induced cholestasis in rodents is caused by hepatic downregulation of transporters, including the basolateral Na+-dependent taurocholate transporter (ntcp) and the canalicular bile salt export pump (bsep) and multidrug resistance-associated protein 2 (mrp2). Details about the regulation of the human transporter proteins during this process are lacking. We used precision-cut human and rat liver slices to study the regulation of transporter expression during LPS-induced cholestasis. We investigated the effect of LPS on nitrate/nitrite and cytokine production in relation to the expression of inducible nitric oxide synthase, NTCP, BSEP, and MRP2 both at the level of mRNA with RT-PCR and protein using immunofluorescence microscopy. In liver slices from both species, LPS-induced expression of inducible nitric oxide synthase was detected within 1-3 h and remained increased over 24 h. In rat liver slices, this was accompanied by a significant decrease of rat ntcp and mrp2 mRNA levels, whereas bsep levels were not affected. These results are in line with previous in vivo studies and validate our liver slice technique. In LPS-treated human liver slices, NTCP mRNA was downregulated and showed an inverse correlation with the amounts of TNF-alpha and Il-1beta produced. In contrast, MRP2 and BSEP mRNA levels were not affected under these conditions. However, after 24-h LPS challenge, both proteins were virtually absent in human liver slices, whereas marker proteins remained detectable. In conclusion, we show that posttranscriptional mechanisms play a more prominent role in LPS-induced regulation of human MRP2 and BSEP compared with the rat transporter proteins.
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PMID:LPS-induced downregulation of MRP2 and BSEP in human liver is due to a posttranscriptional process. 1520 15

Homocysteine (Hcy), an intermediate in methionine metabolism, has been proposed to be involved in hepatic fibrogenesis. Impaired liver function can alter Hcy metabolism. The aim of the present study was to determine plasma Hcy alterations in acute obstructive cholestasis and the subsequent biliary cirrhosis. Cholestasis was induced by bile duct ligation and sham-operated and unoperated rats were used as controls. The animals were studied on the days 7th, 14th, 21st and 28th after the operation. Plasma Hcy, cysteine, methionine, nitric oxide (NO) and liver S-adenosyl-methionine (SAM), S-adenosyl-homocysteine (SAH), SAM to SAH ratio and glutathione were measured. Chronic L-NAME treatment was also included in the study. Plasma Hcy concentrations were transiently elevated by the day 14th after bile duct ligation (P < 0.01) and subsequently returned to control levels. Similar relative fluctuations in plasma Hcy were observed in BDL rats after intraperitoneal methionine overload. Plasma methionine, cysteine and nitrite and nitrate were significantly increased after bile duct ligation. SAM to SAH ratio was diminished by the 1st week of cholestasis and remained significantly decreased throughout the study. These events were accompanied by a decrease in GSH to GSSG ratio in the liver. Chronic L-NAME treatment improved SAM to SAH ratio and prevented the elevation of plasma Hcy and methionine (P < 0.05) while couldn't influence the other parameters. In conclusion, this study demonstrates alterations in plasma Hcy and liver SAM and SAH contents in precirrhotic stages and in secondary biliary cirrhosis, for the first time. In addition, we observed that plasma Hcy concentrations in BDL rats follow a distinct pattern of alteration from what has been previously reported in other models of cirrhosis. NO overproduction may contribute to plasma Hcy elevation and liver SAM depletion after cholestasis.
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PMID:Homocysteine alterations in experimental cholestasis and its subsequent cirrhosis. 1576 80

The aim of the present work was to investigate the role of inducible nitric oxide (NO) synthase (iNOS) in CCl(4)-induced cirrhosis by utilizing iNOS knock out mice (iNOS(-/-)). Cirrhosis was produced by i.p. administration of CCl(4) (1 ml kg(-1) of body weight) dissolved in olive oil three times a week for 3 months to iNOS(-/-) or iNOS(+/+) (wild type) mice; appropriate olive oil controls were performed. Nitrite plus nitrate levels were lower in iNOS(-/-) compared with iNOS(+/+) mice, but CCl(4) did not produce a significant effect in any mice. Reduced (GSH) glutathione was increased in iNOS(-/-) mice receiving vehicle and in both groups receiving CCl(4); lipid peroxidation increased significantly in iNOS(+/+) but not in iNOS(-/-) mice. Bilirubins, alanine aminotransferase and collagen (measured as the hepatic hydroxyproline content) were increased significantly by the chronic intoxication with CCl(4) in both iNOS(-/-) and iNOS(+/+) mice; importantly there was no difference between these groups. This study clearly suggests that NO derived from iNOS does not participate in cholestasis, necrosis or fibrosis induced by CCl(4) in the mice. The present results are in disagreement with several studies indicating a beneficial or detrimental effect of this molecule utilizing different experimental approaches and in agreement with some studies indicating that NO does not affect liver damage in some models. It must be pointed out that this is the first report in iNOS knock out mice utilizing the chronic model of intoxication with CCl(4); thus, comparisons with other models or approaches are difficult to reconcile.
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PMID:Inducible nitric oxide synthase is not essential for the development of fibrosis and liver damage induced by CCl4 in mice. 1670 56


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