Nary Veal

Hemodynamic and antifibrotic effects of losartan in rats with liver fibrosis and/or portal hypertension

BACKGROUND/AIMS To assess the effects of the early and chronic administration of losartan--a specific angiotensin II receptor antagonist--in the prevention of hepatic fibrosis and portal hypertension. METHODS/RESULTS (1) In CCl(4) rats, losartan at 5 and 10 mg/kg per day significantly decreased portal pressure (-11, -18%, respectively), splenorenal shunt blood flow (-60, -80%) and liver fibrosis (liver hydroxyproline and area of fibrosis) without significant changes in mortality and mean arterial pressure (MAP). (2) In bile duct ligated (BDL) rats, losartan at 5 mg/kg per day significantly decreased portal pressure (-14%), splenorenal shunt blood flow (-70%) and liver fibrosis. Losartan at 10 mg/kg per day significantly worsened liver and renal functions, mortality and liver fibrosis, without significant changes in portal pressure and splenorenal shunt blood flow. Losartan at 5 and 10 mg/kg per day significantly decreased MAP (-24, -30%). (3) In portal vein ligated (PVL) rats, losartan significantly decreased MAP (-12%) but did not change portal pressure or splenorenal shunt blood flow. CONCLUSIONS In BDL and CCl(4) rats, losartan has beneficial effects on splanchnic hemodynamics and liver fibrosis. Losartan might decrease hepatic resistances in fibrotic liver. Losartan decreased MAP except in CCl(4) rats. Higher dosage of losartan had deleterious effects in BDL rats.

Effects of long-term administration of interferon α in two models of liver fibrosis in rats

Abstract Background/Aims: The aim of this study was to assess the effect of the early and chronic administration of interferon α in the prevention of hepatic fibrosis and portal hypertension. Methods: Rats with liver fibrosis due to bile duct ligation or CCl 4 were divided into three groups: sham, placebo and interferon α 2a 100 000 UI/day. Liver fibrosis was assessed by the area of fibrosis (image analysis), liver hydroxyproline and mRNA (fibronectin, procollagen α2(I)) contents, and serum hyaluronate. Systemic and splanchnic hemodynamics were also evaluated. Results: Interferon α significantly decreased fibrosis in the CCl 4 model only: area of fibrosis: 13.9±3.7 vs 10.5±3.3% ( p p r =0.77 in the biliary model and r =0.87 in the CCl 4 model, p p 4 model. No significant effects were observed in rats with biliary fibrosis. Conclusions: The early and chronic administration of interferon α prevents the development of liver fibrosis and porto-collateral circulation in the CCl 4 model but not in the biliary model. However, the antifibrotic effects of interferon need to be confirmed in further studies.

Relationship between vascular reactivity in vitro and blood flows in rats with cirrhosis

In cirrhosis there is a hyperdynamic circulation, which occurs mainly in the systemic and splanchnic regions. Using isolated-vessel models, previous studies have shown reduced aortic reactivity to vasoconstrictors in rats with cirrhosis. The aim of the present study was to evaluate and compare the vascular responsiveness to phenylephrine in arterial rings and the blood flows from different regions in rats with cirrhosis and controls. Reactivity was studied in isolated thoracic aortic, superior mesenteric arterial and carotid arterial rings from sham-operated and bile-duct-ligated rats by measuring the cumulative concentration-dependent tension induced by phenylephrine (10(-9)-10(-4) M). Blood flows were measured by the radioactive microsphere method. In rats with cirrhosis, a significant hyporeactivity to phenylephrine was observed in both the aorta and the superior mesenteric artery compared with the corresponding arteries of normal rats. This hyporesponsiveness was corrected by N(omega)-nitro-L-arginine (0.1 mM). In contrast, carotid artery reactivity and the responses to N(omega)-nitro-L-arginine were similar in the cirrhotic and control groups. In each case, cardiac output and mesenteric arterial blood flow were significantly higher in cirrhotic than in normal rats. Cerebral blood flows were not significantly different between the two groups. In cirrhotic rats, arterial hyporeactivity may be a consequence of increased regional blood flow and increased production of nitric oxide.

Hemodynamic effects of terlipressin and octreotide administration alone or in combination in portal hypertensive rats

BACKGROUND/AIMS The action sites and kinetic effects of octreotide and terlipressin may be different. Therefore, we studied the hemodynamic effects of acute administration of these drugs alone or in combination in rats with portal hypertension due to portal vein ligation. METHODS In a first study performed in anesthetized rats, hemodynamics were measured before and after drug administration (placebo, octreotide: 8 microg x kg(-1) x h(-1) for 30 min, terlipressin: 50 microg/kg bolus, terlipressin + octreotide at the same doses). The second study, performed in conscious rats, included the same groups and drug doses; hemodynamics were measured every 10 min for 1 h. The third study tested the effect of preinfusion of octreotide on responsiveness to terlipressin. RESULTS Terlipressin produced more marked systemic effects than octreotide by decreasing heart rate and cardiac output and increasing mean arterial pressure. Terlipressin produced a greater decrease in portal pressure than octreotide: placebo: -3+/-5%, terlipressin: -42+/-8%, octreotide: -16+/-10%, combination: -44+/-8% (conscious rats at 20 min, p<10(-4)). The decrease in portal pressure was immediate and lasted at least 60 min with both drugs. Octreotide significantly decreased spleno-renal shunt blood flow (% variation): placebo: -6+/-8, terlipressin: -15.5+/-20, octreotide: -22.5+/-20, combination: -27+/-10 (p<10(-2)). Octreotide preinfusion significantly increased the responsiveness of arterial pressure and heart rate to terlipressin. CONCLUSIONS Terlipressin decreases portal pressure significantly more than octreotide, while only octreotide significantly decreases collateral blood flow. Simultaneous administration of these drugs does not have significant additive effects but has complementary effects. The preadministration of octreotide alters systemic response to terlipressin.

Effects of octreotide on intestinal transit and bacterial translocation in conscious rats with portal hypertension and liver fibrosis

In cirrhosis, delayed intestinal transit may be responsible for increased endoluminal bacterial overgrowth and increased bacterial translocation. Octreotide has been reported to reduce intestinal transit. Therefore, we evaluated whether octreotide administration influences bacterial translocation in a model of liver fibrosis secondary to dimethylnitrosamine (DMNA) administration. Twenty-nine conscious rats were randomly assigned to three groups (sham rats + placebo as controls, DMNA + placebo, DMNA + octreotide, 1.5 μg/kg thrice daily subcutaneously), and including portal pressure, intestinal transit (radioactive method), and bacterial translocation were measured. Three of four variables measuring intestinal transit suggested a significant delay in intestinal transit in DMNA rats compared to controls (eg, cumulated radioactivity 50%: controls: 5.3 ± 1.5, DMNA + placebo: 3.2 ± 1.2, DMNA + octreotide: 2.7 ± 1.9, P < 0.01). This delay tended to be enhanced by octreotide but the effect was only significant with one of the intestinal transit variables. Bacterial translocation was significantly increased in DMNA rats compared to controls but octreotide did not increase translocation [eg, germ count (log) in lymph nodes: controls: 3.1 ± 3.6, DMNA + placebo: 12.3 ± 4.4, DMNA + octreotide: 10.6 ± 6.0, P < 0.001]. There was no significant correlation of portal pressure, intestinal transit, and bacterial translocation in this study. In conclusion, our results show that, although octreotide worsens delayed intestinal transit, it has no influence on the level of bacterial translocation.

Spleno-renal shunt blood flow is an accurate index of collateral circulation in different models of portal hypertension and after pharmacological changes in rats

BACKGROUND/AIMS Recently, we developed a new method to measure collateral blood flow in rats: splenorenal shunt (SRS) blood flow (BF). The aims were to evaluate the reproducibility of SRSBF measurement in different models of portal hypertension, and to investigate the ability of SRSBF to disclose pharmacological changes. METHODS Hemodynamics were determined in anesthetized rats with secondary biliary, CCl4 or DMNA cirrhosis and portal vein ligation (PVL) under baseline and pharmacological (octreotide, vapreotide) conditions. The main measurements performed were: SRSBF by the transit time ultrasound (TTU) method and % portosystemic shunts (PSS) by the microsphere method. RESULTS SRSBF was 6 to 10 times higher in portal hypertensive rats and was similar in the different models of cirrhosis but was higher in portal vein ligated rats than in cirrhotic rats (1.1+/-0.7 vs 0.6+/-0.7 ml x min(-1) x 100 g(-1), p=0.01). SRSBF was correlated with mesenteric %PSS (r=0.61, p<0.01), splenic %PSS (r=0.54, p<0.05), portal pressure (r= 0.32, p<0.05) and the area of liver fibrosis (r=0.33, p<0.05). Octreotide significantly decreased SRSBF (-23+/-20%, p<0.01 vs placebo: -6+/-8%, NS). Vapreotide significantly decreased SRSBF but not mesenteric or splenic %PSS compared to placebo. The variations in SRSBF (-26+/-32%) and in splenic %PSS (0+/-15%) with vapreotide were significantly different (p<0.05) and not correlated (r=-0.1, NS). CONCLUSIONS Determination of SRSBF by TTU is an accurate way to measure collateral blood flow in different models of intra- and extra-hepatic portal hypertension in rats. Its sensitivity provides accurate measurement of pharmacological changes, unlike the traditional estimation of %PSS by the microsphere method.

Long-term administration of PGE1 increases liver fibrosis and collateral blood flow in bile-duct-ligated rats

BACKGROUND/AIMS The aim of this study was to assess the effect of early and chronic administration of a prostaglandin E1 analogue (misoprostol) in the prevention of liver fibrosis and portal hypertension. METHODS Liver fibrosis was induced by bile duct ligation. Controls had a sham operation. Bile-duct-ligated rats were divided into two groups: placebo (vehicle only) and misoprostol (10 microg/d by gavage) for 4 weeks after surgery. Liver fibrosis was assessed by the area of fibrosis (image analysis), liver hydroxyproline content and serum hyaluronate. Systemic and splanchnic hemodynamics were evaluated including spleno-renal shunt blood flow by the transit-time ultrasound technique. RESULTS Mean arterial pressure was significantly lower in the misoprostol group (p<0.01). There was an unexpected increase in fibrosis parameters in the misoprostol group compared to the placebo group, e.g. area of fibrosis: 9.5+/-4.0 vs 15.0+/-8.1% (p<0.05). Spleno-renal shunt blood flow was significantly higher in the misoprostol group than in the placebo group (4.6+/-3.7 vs 2.2+/-2.0 ml/min, p<0.05) while portal pressure was unchanged. CONCLUSIONS The early and chronic administration of misoprostol enhances porto-collateral circulation blood flow and the development of liver fibrosis in bile-duct-ligated rats.

Hemodynamic effects of acute and chronic administration of vapreotide in rats with cirrhosis.

The aim of this study was to assess the hemodynamic effects of acute and chronic administration of vapreotide, a somatostatin analog, in rats with intrahepatic portal hypertension induced by dimethylnitrosamine (DMNA) administration. Acute effects were evaluated at baseline and 30 min after placebo (N = 13) or vapreotide (8 μg/kg/hr, N = 13) infusions in DMNA rats. Chronic hemodynamic effects were evaluated using subcutaneous implants for five weeks in anesthetized DMNA rats (placebo: N = 13, vapreotide: N = 13) and in sham rats (placebo: N = 10, vapreotide: N = 10). Hemodynamic measurements included splenorenal shunt blood flow (SRS BF) by the transit time ultrasound (TTU) method and cardiac output by the combined dilution–TTU method. Acute administration of vapreotide significantly decreased SRS BF (−17.3 ± 19 vs −1.1 ± 14%, P < 0.05) and portal pressure (−8 ± 9 vs 0 ± 8%, p < 0.05) compared to placebo without systemic effects. Chronic administration of vapreotide significantly reduced the increase in SRS BF (2.4 ± 1.5 vs 1.2 ± 1.0 ml/min, P < 0.05) and cardiac index (50 ± 15 vs 33 ± 10 ml/min/100 g, P < 0.0001) while portal pressure and blood flow, and mean arterial pressure were not significantly changed compared to placebo. In conclusion, the acute administration of vapreotide decreased collateral circulation blood flow while chronic administration attenuated its development. Vapreotide seems to have a vasoconstrictive effect on collateral circulation.