Renal effects of the novel selective adenosine A1 receptor blocker SLV329 in experimental liver cirrhosis in rats.

Liver cirrhosis is often complicated by an impaired renal excretion of water and sodium. Diuretics tend to further deteriorate renal function. It is unknown whether chronic selective adenosine A(1) receptor blockade, via inhibition of the hepatorenal reflex and the tubuloglomerular feedback, might exert diuretic and natriuretic effects without a reduction of the glomerular filtration rate. In healthy animals intravenous treatment with the novel A(1) receptor antagonist SLV329 resulted in a strong dose-dependent diuretic (up to 3.4-fold) and natriuretic (up to 13.5-fold) effect without affecting creatinine clearance. Male Wistar rats with thioacetamide-induced liver cirrhosis received SLV329, vehicle or furosemide for 12 weeks. The creatinine clearance of cirrhotic animals decreased significantly (-36.5%, p<0.05), especially in those receiving furosemide (-41.9%, p<0.01). SLV329 was able to prevent this decline of creatinine clearance. Mortality was significantly lower in cirrhotic animals treated with SLV329 in comparison to animals treated with furosemide (17% vs. 54%, p<0.05). SLV329 did not relevantly influence the degree of liver fibrosis, kidney histology or expression of hepatic or renal adenosine receptors. In conclusion, chronic treatment with SLV329 prevented the decrease of creatinine clearance in a rat model of liver cirrhosis. Further studies will have to establish whether adenosine A(1) receptor antagonists are clinically beneficial at different stages of liver cirrhosis.

Effectiveness of recombinant human serum albumin in the treatment of ascites in liver cirrhosis: evidence from animal model.

1. To investigate the effectiveness of recombinant human serum albumin (rHSA) in the treatment of ascites in liver cirrhosis, we examined its effect on rats with carbon tetrachloride-induced liver cirrhosis. 2. Twenty-five percent rHSA was administered intravenously at a dose of 0.25 to 1.0 g/kg for 2 days to rats with liver cirrhosis accompanied by ascites retention and hypoalbuminemia. 3. rHSA dose dependently decreased abdominal circumference, a clinical index of ascites, with significant difference at a dose of 1.0 g/kg. 4. Although there was no significant difference, rHSA increased blood colloid osmotic pressure (b-COP) and urine volume (UV) in a nearly dose-dependent manner, with significant negative correlation between changes from baseline value in these parameters and in abdominal circumference. 5. These findings suggest that rHSA has abdominal circumference-decreasing action associated with b-COP improvement and UV increase and that it could be effective as a therapeutic drug for ascites in patients with liver cirrhosis accompanied by hypoalbuminemia.

Urinary excretion of the collagen cross-link pyridinoline increases during liver fibrogenesis.

BACKGROUND/AIMS: Pyridinoline, a specific cross-link of mature collagen, increases in liver during fibrogenesis and its hepatic level is related to the degree of reversibility of the fibrotic process. Since pyridinoline is excreted in urine, we have investigated the relationship between its urinary level and liver fibrogenesis in a model of mild and reversible liver fibrosis, murine schistosomiasis. METHODS: Pyridinoline was measured by HPLC in urine and in liver of Schistosoma mansoni-infected mice during the acute and the chronic phases of the infection. Collagen deposition was measured colorimetrically. Both the isolated granulomas and the surrounding liver parenchyma were analyzed. RESULTS: In infected mice, pyridinoline increased mainly in the isolated granulomas, corresponding to the fibrotic lesions, and slightly in the surrounding parenchyma. The urinary excretion of pyridinoline increased during liver fibrogenesis and was correlated to the duration of infection (r=0.81) and to the collagen content of granulomas (r=0.81). The treatment of infected mice by praziquantel, an antiparasitic drug, did not lead to significant changes in liver collagen cross-linking by pyridinoline either in granulomas or in parenchyma. The major effect of the drug was targeted at the collagen content of parenchyma, which decreased by 50%, 18 weeks after treatment. The urinary level of pyridinoline of treated mice was negatively correlated to the length of the treatment follow-up (r=-0.76). CONCLUSIONS: The measurement of the urinary excretion of pyridinoline could be helpful to monitor the remodeling of liver extracellular matrix occurring in fibrogenesis and the effect of chemotherapy.

Blunted natriuretic response to human urine extracts with Na+,K(+)-ATPase inhibiting activity in experimental cirrhosis.

Human urine and plasma extracts contain a material that inhibits the enzyme Na+,K(+)-ATPase (the endogenous sodium pump) and produces natriuresis in the bioassay animal. This endogenous sodium pump inhibitor(s), also known as digitalis-like factor, is thought to be involved in sodium and extracellular fluid volume homeostasis. Increased urine and plasma sodium pump inhibiting activity have been reported in patients with cirrhosis and sodium retention. The aim of the study was to assess the renal response to i.v. administration (0.2 ml/min per kg bw for 10 min) of a human urine extract containing sodium pump inhibiting activity (28.5 nmol equivalent ouabain/ml) in eight conscious rats with cirrhosis and ascites and eight control rats. Baseline urinary excretion of Na+,K(+)-ATPase inhibiting activity was significantly higher in cirrhotic rats with ascites than in control rats (235 +/- 40 vs 91 +/- 16; p < 0.01). Human urine extract induced a significant (p < 0.05) increase in glomerular filtration rate in control (3.2 +/- 0.4 to 4.2 +/- 0.5 ml/min) and cirrhotic rats (3.0 +/- 0.3 to 4.0 +/- 0.5 ml/min). In control rats it also increased urinary sodium excretion (1.47 +/- 0.22 to 2.43 +/- 0.5 microEq/min, p < 0.01) and fractional sodium excretion (0.29 +/- 0.01 to 0.43 +/- 0.04%, p < 0.025). In contrast, in cirrhotic rats with ascites neither sodium excretion nor fractional sodium excretion was significantly affected. No changes were observed in plasma aldosterone and atrial natriuretic peptide concentrations in either group. These data suggest that in cirrhosis there is a renal resistance to the natriuretic effect of endogenous sodium pump inhibitor(s).

[Changes in renal kaliuretic function in the dynamics of hepatic cirrhotic transformation]. / Izmenenie kaliiureticheskoi funktsii pochek v dinamike tsirroticheskoi transformatsii pecheni.

During formation of hepatic cirrhosis in animals, excessive potassium loss has been found to depend on the increased loading of a nephron by its cation at its early stage and on abnormally changed tubular processes at late stages.

Serial natriuretic response to atrial peptide in preascitic bile duct ligated dogs.

We determined if nine precirrhotic unanaesthetized dogs with chronic bile duct ligation (CBDL) responded uniformly to atrial natriuretic peptide (ANF) by infusing this peptide sequentially over 8-12 weeks at 175 ng.kg-1.min-1 and observing the natriuretic response. ANF was administered every 2 weeks post-CBDL until the 8th week and given again during the cirrhotic phase with ascites present (10-12 weeks post-CBDL). Sodium balance studies were conducted at similar time intervals. During the control period and at weeks, 2, 6, and 8 post-CBDL all dogs responded to ANF with a significant change in sodium excretion (delta UNaV, 50-240 mu equiv./min). At these times, all dogs were in sodium balance. At week 4 and during the ascitic period, heterogeneity of response to ANF was observed. In the former interval, five dogs responded (delta UNaV,75-230 mu equiv./min) and four did not, while in the latter interval, five dogs responded (delta UNaV, 50-240 mu equiv./min) and three did not (one dog died). In both time periods, there was severe urinary sodium retention (daily UNaV, 11 +/- 3 and 2 +/- 1 mequiv./day, respectively) while the dogs were ingesting 45 mequiv.Na+/day. The heterogeneity of natriuretic response was not correlated to plasma immunoreactive ANF, renin, or aldosterone levels. Plasma volume was significantly expanded from control during both intervals. We conclude that there is transient sodium retention during the 4th week post-CBDL, and that this period is associated with the heterogeneity of natriuretic response to ANF, despite the absence of ascites or edema.

Impaired natriuretic response to atrial natriuretic peptide in the isolated kidney of rats with experimental cirrhosis.

1. Sodium retention in cirrhosis may be partly attributable to resistance to a putative circulating natriuretic factor. In cirrhosis, plasma concentrations of atrial natriuretic peptide are often increased in the presence of sodium retention. 2. In order to determine whether the kidney of cirrhotic animals may be insensitive to atrial natriuretic peptide, isolated perfused kidneys from six cirrhotic and five control rats were exposed to increasing concentrations of atrial natriuretic peptide. Cirrhosis had been induced by carbon tetrachloride administration. 3. Excretion in vivo of a 2 mmol sodium load, administered by gavage, was impaired in cirrhotic animal for up to 4 h as compared with control animals (4.2 +/- 1.9 vs 34.9 +/- 13.4% P less than 0.05). 4. During perfusion at 110 mmHg in the absence of atrial natriuretic peptide, sodium excretion by isolated kidneys of cirrhotic animals tended to be lower than in control animals, but the difference was not significant (4.93 +/- 1.01 vs 8.41 +/- 1.48 mumol min-1 g-1 kidney weight, P = 0.09). There was a smaller increase in urinary sodium excretion by the kidneys of cirrhotic rats compared with control rats in the presence of atrial natriuretic peptide at 10, 50 and 200 pmol/l (respectively: 0.06 +/- 0.08 vs 1.29 +/- 0.35 mumol/min-1 g-1 kidney weight, P less than 0.02; 0.49 +/- 0.08 vs 1.82 +/- 0.42 mumol min-1 g-1 kidney weight, P less than 0.03; 1.42 +/- 0.16 vs 3.23 +/- 0.73 mumol min-1 g-1 kidney weight, P less than 0.05), but not at 1000 pmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative study of aminoglycoside nephrotoxicity in normal rats and rats with experimental cirrhosis.

Several authors have suggested that the risk of developing aminoglycoside nephrotoxicity is greater in cirrhotic patients than in the noncirrhotic population. However, this has not been confirmed by other investigators. To compare the intensity and characteristics of aminoglycoside nephrotoxicity in cirrhotic and normal rats, 31 rats with carbon tetrachloride-induced cirrhosis with ascites and 35 control rats were treated with gentamicin. Each group of rats was divided into two subgroups in order to receive 10 or 40 mg per kg per day of gentamicin, and different subsets of animals were killed on Days 4, 8 and 12 of treatment for renal histological examination and determination of renal tissue gentamicin concentration. Urine volume, osmolality, sodium excretion and N-acetyl-beta-D-glucosaminidase activity were measured daily throughout the study. Creatinine clearance and trough plasma concentration of gentamicin were determined in each animal immediately before killing. There were no significant differences between cirrhotic and control rats in relation to the magnitude of changes in urine volume, osmolality, sodium excretion and N-acetyl-beta-D-glucosaminidase activity and creatinine clearance during gentamicin administration. The values of a histopathological score semiquantitatively assessing the renal morphological changes observed by light microscopy were not significantly different in cirrhotic and control rats. In addition, similar trough plasma and renal cortical tissue concentrations of gentamicin were observed in both groups of animals. These results suggest that, in this experimental model, cirrhosis does not increase the risk for aminoglycoside nephrotoxicity.

Temporal relationship between hyperaldosteronism, sodium retention and ascites formation in rats with experimental cirrhosis.

To investigate the role of aldosterone in sodium retention and ascites in cirrhosis, the urinary sodium excretion, sodium balance and urinary excretion of aldosterone-18-glucuronide (UAldV) were serially measured in 11 rats undergoing cirrhosis induction with carbon tetrachloride (CT) and phenobarbital (CT rats) and in 10 control rats which received phenobarbital. All CT rats developed ascites, seven within the ninth week after starting the program and four within the 10th week. One week before the onset of ascites, CT rats and control rats were different with respect to sodium excretion (1.41 +/- 0.15 vs. 1.82 +/- 0.1 mEq per day), sodium balance (0.57 +/- 0.12 vs. 0.20 +/- 0.09 mEq per day) and UAldV (67.8 +/- 9.5 vs. 25.7 +/- 1.7 ng per day). These differences were more pronounced within the week in which ascites was detected in CT rats. Before these 2 weeks, both groups did not differ with respect to these parameters. In the 132 urine samples obtained in CT rats, there was a correlation between sodium excretion and UAldV (r = -0.53; p less than 0.001). Twenty-one additional CT rats were divided into two groups. Eleven animals were given spironolactone (20 mg per day s.c. in olive oil) from the 6th week, and 10 only received olive oil. Thirteen weeks after starting the program, all rats not treated with spironolactone had sodium retention and ascites (in five rats, ascites appeared within the ninth week and in five within the tenth week); this occurred in only one animal treated with spironolactone.(ABSTRACT TRUNCATED AT 250 WORDS)

[Xanthurenuria at different stages of liver lesion induced by protein and choline deficiency]. / Izuchenie ksanturenurii na razlichnykh stadiiakh povrezhdeniia pecheni, vyzbannogo defitsitom belka i kholina.

The parallelism between xanthurenuria and liver affections caused by protein and choline deficiency was studied. At the stages marking the development of lipohepatosis and fibrosis there occurred an intensive passage of xanthurenic acid. The intensity of xanthurenuria at the stage marking the appearance of hyperplastic nodes continued to gain strength. With progressive advance of pathological changes, which by the 9--12th months of the experiment reached the stage of a fully developed nodular cirrhosis xanthurenuria gradually stopped.

Urinary excretion of alpha-fetoprotein in rats on a cirrhogenic carbon tetrachloride regimen.

Alpha-fetoprotein was detected in the serum and urine of 2- to 9-mth-old rats subjected to protracted CCl4 poisoning. During the first 3 mth of the experiment, urinary excretion of AFP was found in 30-40 per cent. of the animals, increasing to 70 per cent. thereafter. The liver lesions progressed from acute parenchymal necrosis to cirrhosis, but hepatocellular carcinomas did not develop. Uptake of tritiated thymidine by the hepatocytes increased significantly but was constant throughout the experimental period. The findings are compared to the observations made during 3mDAB-induced hepatocarcinogenesis in the rat.