Acute troglitazone action in isolated perfused rat liver.
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1. The thiazolidinedione compound, troglitazone, enhances insulin action and reduces plasma glucose concentrations when administered chronically to type 2 diabetic patients. 2. To analyse to what extent thiazolidinediones interfere with liver function, we examined the acute actions of troglitazone (0.61 and 3.15 microM) on hepatic glucose and lactate fluxes, bile secretion, and portal pressure under basal, insulin- and/or glucagon-stimulated conditions in isolated perfused rat livers. 3. During BSA-free perfusion, high dose troglitazone increased basal (P < 0.01), but inhibited glucagon-stimulated incremental glucose production by approximately 75% (10.0 +/- 2.5 vs control: 40.0 +/- 7.2 micromol g liver(-1), P < 0.01). In parallel, incremental lactate release rose approximately 6 fold (13.1 +/- 5.9 vs control: 2.2 +/- 0.8 mmol g liver(-1), P < 0.05), while bile secretion declined by approximately 67% [0.23 +/- 0.02 vs control: 0.70 +/- 0.05 mg g liver(-1) min(-1)), P < 0.001]. Low dose troglitazone infusion did not enhance the inhibitory effect of insulin on glucagon-stimulated glucose production, but rapidly increased lactate release (P < 0.0005) and portal venous pressure (+0.17 +/- 0.07 vs +0.54 +/- 0.07 cm buffer height, P < 0.0001). 4. These results indicate that troglitazone exerts both insulin-like and non-insulin-like hepatic effects, which are blunted by addition of albumin, possibly due to troglitazone binding. (+info)
Role of Kupffer cells in the release of nitric oxide and change of portal pressure after ethanol perfusion in the rat liver.
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The objective of this study was to elucidate the role of Kupffer cells during the increase of portal vein pressure caused by ethanol. We measured nitric oxide (NO) in the perfused rat liver using a commercial NO meter. Ethanol perfusion increased NO release and portal vein pressure. Gadolinium chloride pretreatment reduced the increase in portal vein pressure during the early phase of ethanol perfusion, but did not affect the release of NO after ethanol infusion. These findings suggest that Kupffer cells play an important role in liver microcirculation during the early stage of ethanol intake, but that the mechanism may not be regulated by NO. (+info)
Sodium handling in patients with well compensated cirrhosis is dependent on the severity of liver disease and portal pressure.
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BACKGROUND AND AIMS: To test the contribution of portal pressure gradient (PPG) and neurohumoral factors to sodium handling in cirrhotic patients without ascites, by comparing preascitic cirrhotic patients with patients with transjugular intrahepatic portosystemic stent shunt (TIPSS) and previous ascites. PATIENTS: Ten patients with TIPSS and 10 preascitic cirrhotic patients. METHODS: Changes in glomerular filtration, renal plasma flow, urinary sodium excretion (U(Na)V), and neurohumoral factors were measured before and for two hours after infusion of one litre of 0. 9% saline over one hour. RESULTS: Glomerular filtration rate and renal plasma flow were significantly higher in patients with TIPSS compared with preascitic cirrhotic patients. Following saline infusion both parameters increased significantly; this increase was significantly greater in patients with TIPSS. U(Na)V increased significantly in both groups following saline infusion. The increase in U(Na)V was significantly greater in the TIPSS group. Plasma renin activity and angiotensin II decreased significantly in both groups. Basal U(Na)V was independently correlated with angiotensin II concentration and PPG and the change in U(Na)V correlated with the PPG. CONCLUSIONS: Results suggest that patients with advanced liver disease and low portal pressure handle sodium as well as patients with compensated liver disease and high portal pressure. These results are consistent with the notion that in addition to peripheral vasodilatation and severity of liver disease, the severity of portal hypertension contributes to the abnormalities of sodium retention in cirrhosis. (+info)
Effects of insulin-like growth factor I on basal and stimulated glucose fluxes in rat liver.
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Effects of insulin-like growth factor I (IGF-I) and insulin on glucose and potassium fluxes were examined by measuring transhepatic glucose and potassium balance in isolated perfused rat livers. At 1 nM, both IGF-I and insulin decreased basal glucose release by approximately 64% (P < 0.05). Adrenaline (epinephrine)-stimulated glucose release (42.6 +/- 4.5 micromol/g of liver within 30 min) was inhibited (P < 0.05) by approximately 32 and approximately 52% during IGF-I and insulin exposure, which was accompanied by reduced cAMP release (-71 and -80%, P < 0.05). IGF-I- and insulin-induced reduction of glucose release only decreased during calcium-free perfusion, but not during inhibition of phosphoinositide 3-kinase by wortmannin. Both IGF-I and insulin induced net potassium uptake, while insulin also attenuated the response to adrenaline. In conclusion, IGF-I causes (i) insulin-like inhibition of hepatic glycogenolysis, even at low, nanomolar concentrations, which is associated with decreased cAMP release, reduced in the absence of Ca(2+), but not mediated by phosphoinositide 3-kinase, (ii) reduction of adrenaline-induced glycogenolysis and (iii) net potassium uptake under basal conditions. (+info)
In vivo gene transfer of endothelial nitric oxide synthase decreases portal pressure in anaesthetised carbon tetrachloride cirrhotic rats.
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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. (+info)
Acute propranolol administration effectively decreases portal pressure in patients with TIPS dysfunction. Transjugular intrahepatic portosystemic shunt.
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BACKGROUND AND AIMS: Up to 60% of patients treated with transjugular intrahepatic portosystemic shunt (TIPS) require angioplasty or restenting during the first year of follow up because of TIPS dysfunction (stenosis of the intrahepatic shunt increasing the portal pressure gradient above the 12 mm Hg threshold). We hypothesised that in patients with TIPS stenosis, propranolol administration, by decreasing portal inflow, would markedly decrease portal pressure. PATIENTS AND METHODS: Eighteen patients with TIPS dysfunction were investigated by measuring portal pressure gradient before and after acute propranolol administration (0.2 mg/kg intravenously; n=18). RESULTS: Propranolol markedly reduced the portal pressure gradient (from 16.6 (3.5) to 11.9 (4.8) mm Hg; p<0.0001), cardiac index (-26 (7)%), and heart rate (-18 (7)%) (p<0.0001). Portal pressure gradient decreased to less than 12 mm Hg in nine patients, more frequently in those with moderate dysfunction (portal pressure gradient 16 mm Hg) than in patients with severe dysfunction (portal pressure gradient >16 mm Hg) (8/10 v 1/8; p=0.015). CONCLUSIONS: Propranolol therapy may delay the increase in portal pressure and reduce the need for reintervention in patients with TIPS dysfunction. (+info)
Hepatic venous pressure gradient measurements to assess response to primary prophylaxis in patients with cirrhosis: a decision analytical study.
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BACKGROUND: The measurement of the hepatic venous pressure gradient may identify a suboptimal response to beta-blockers in patients with varices at risk for bleeding. However, the cost-effectiveness of routine hepatic venous pressure gradient measurements to guide primary prophylaxis has not been examined. METHODS: We used decision analysis to evaluate two hepatic venous pressure gradient measurement strategies relative to standard beta-blocker therapy in a hypothetical cohort of patients with high-risk varices: (i) hepatic venous pressure gradient measurement 4 weeks after the initiation of beta-blocker therapy; and (ii) hepatic venous pressure gradient measurement prior to and 4 weeks after the initiation of beta-blocker therapy. The total expected costs, variceal bleeding episodes and deaths were calculated over a 1-year time horizon. RESULTS: Beta-blocker therapy was associated with total costs of $1464, seven variceal bleeding episodes, one variceal bleeding episode-related death and 15 deaths. One hepatic venous pressure gradient measurement was associated with total costs of $5015, four variceal bleeding episodes, one variceal bleeding episode-related death and 15 deaths. Two hepatic venous pressure gradient measurements were associated with total costs of $8657, four episodes of variceal bleeding, one variceal bleeding episode-related death and 15 deaths. Compared with beta-blocker therapy alone, the incremental costs per variceal bleeding episode prevented and death averted were, respectively, $108 185 and $355 100 (one hepatic venous pressure gradient measurement) and $202 796 and $719 300 (two hepatic venous pressure gradient measurements). The results were sensitive to the time horizon of the analysis, the probability of bleeding whilst on beta-blockers and the cost of hepatic venous pressure gradient measurement. CONCLUSION: Hepatic venous pressure gradient measurement to guide primary prophylaxis is an expensive strategy for reducing variceal bleeding or death, especially in patients with limited life expectancy, such as those with advanced, decompensated cirrhosis. (+info)
Systemic and regional changes in plasma endothelin following transient increase in portal pressure.
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An acute increase in portal pressure or reduction in portal inflow has been shown to decrease renal plasma flow (RPF). The aim of the study was to evaluate regional and systemic hemodynamics after acute occlusion of a transjugular intrahepatic portosystemic stent-shunt (TIPSS) and study the effect of the same on plasma endothelin (ET-1) levels in the systemic circulation, renal vein, and hepatic vein. Sixteen patients attending for portography after previous TIPSS placement were studied. The shunt was acutely occluded with an angioplasty balloon for 12 minutes. Changes in portal pressure gradient (PPG), hepatic plasma flow (HPF), RPF, cardiac output (CO), and systemic vascular resistance (SVR) were measured before and after shunt occlusion. Blood was collected from the femoral artery and hepatic and renal veins for ET-1 measurement. At T = 0, SVR correlated with circulating arterial ET-1 level (r = 0.74; P <.05). After shunt occlusion (T = 12 minutes), heart rate, CO, and mean arterial pressure decreased (P <.05), whereas PPG increased (P <.05). RPF decreased from 485 +/- 55 to 282 +/- 47 mL/min (P <.01), whereas HPF increased from 700 +/- 39 to 779 +/- 33 mL/min (P <.001). There was a significant increase in arterial concentration and renal production, and decrease in hepatic production of ET-1. Veno-arterial (V-A) concentration difference in ET-1 level in the renal vein, as well as renal flux of ET-1, increased significantly, whereas hepatic vein V-A concentration difference and hepatic flux of ET-1 decreased significantly. At T = 12 minutes, ET-1 renal output correlated negatively with RPF (r = 0.72; P <.05). Results of this study show that an acute increase in portal pressure and reduction in portal inflow brought about by occlusion of a TIPSS shunt decreases RPF and increases HPF. These hemodynamic changes are accompanied by increases in arterial, renal vein, and hepatic vein ET-1 concentrations, which may possibly mediate the observed findings. (+info)