Antihypercholesterolemic effect of dipyridamole in chickens.

The administration of a 4 mg/kg dose of dipyridamole daily in chickens fed a diet supplemented with 2% cholesterol reversed the hypercholesterolemic effects of the diet. In particular, it reduced the plasma cholesterol concentration in approximately 18%; the levels of very-low-density lipoproteins and intermediate-density lipoproteins and the liver cholesterol content. Although the mechanism was not fully elucidated, the increased excretion of cholesterol seemed to be responsible for the lipid lowering effect. When dipyridamole was administered in chickens fed the same diet without cholesterol no significant changes were observed. Inasmuch as the chicken lipoprotein metabolism differs in several aspects to human, the extrapolation of the hypocholesterolemic effect of dipyridamole to man must be made with care.

Involvement of glucocorticoids in the stimulation of rat kidney phosphoenolpyruvate carboxykinase activity after liver intoxication by carbon tetrachloride.

The enhancement of rat kidney cortex phosphoenolpyruvate carboxykinase activity during acute liver intoxication by carbon tetrachloride (CCl4) did not appear to be related to metabolic acidosis. Blood glucocorticoids were higher in CCl4-treated animals than in controls. Adrenalectomy fully counteracted the stimulation of renal phosphoenolpyruvate carboxykinase activity and gluconeogenic capacity brought about by CCl4 administration. It is concluded that glucocorticoids are involved in the renal response to acute liver intoxication by CCl4.

Dissociation between renal gluconeogenesis and ammoniagenesis after acute liver intoxication.

Renal glucose and ammonia production as well as phosphoenolpyruvate carboxykinase and phosphate-dependent glutaminase activities were measured for acute liver intoxication. Gluconeogenesis and phosphoenolpyruvate carboxykinase activity increased, whereas ammonia production and phosphate-dependent glutaminase showed no changes with respect to the controls. The dissociation between gluconeogenesis and ammoniagenesis may be explained by the differential effect on the enzymes in these conditions.

Plasma polyunsaturated fatty acids in liver cirrhosis with or without chronic hepatic encephalopathy: a preliminary study.

Fatty acid levels (from C14:0 to C22:6n3) in plasma lipid fractions were prospectively studied in 11 cirrhotic patients with chronic hepatic encephalopathy and compared with those in 23 cirrhotic patients without chronic hepatic encephalopathy with similar age, sex distribution, and liver and nutritional status, and in 11 age- and sex-matched, healthy subjects. Plasma lipid fractions were separated by thin-layer chromatography and fatty acids were identified by capillary column gas-liquid chromatography. Total n6 polyunsaturated fatty acid plasma levels were lower in cirrhotic patients--with and without chronic hepatic encephalopathy--than in control subjects. In addition, arachidonic acid levels, both in total lipids and fractions, were lower in patients with than in those without chronic encephalopathy. On the other hand, a selective decrease of plasma docosahexaenoic acid (a major component of neuronal membranes) was observed in those patients with chronic encephalopathy as compared with both control and cirrhotic subjects without chronic encephalopathy. These findings may be due to various mechanisms. Differences in long-chain polyunsaturated fatty acid content in fish- and meat-restricted diets partly may account for these findings. However, it could be speculated that polyunsaturated fatty acid biosynthesis may be reduced further in patients with chronic hepatic encephalopathy because of either a decrease in portal essential fatty acid extraction in the postabsorptive phase due to portal-systemic shunting or to the effect of protein-restricted diets. Furthermore, the finding of low plasma docosahexaenoic acid in these patients raises the possibility that this deficiency might be an additional pathogenic factor in chronic hepatic encephalopathy.

Acid-soluble nucleotides of cow's, goat's and sheep's milks, at different stages of lactation.

The acid-soluble ribonucleotides of cow's, goat's and sheep's milks were measured by enzymic and ion-exchange chromatographic procedures at different stages of lactation. Colostra and milk from ruminant species contained orotic acid and 13 well-identified nucleotides: AMP, CMP, GMP, UMP, UDP, GDP, UDP-glucose, UDP-galactose, UDP-N-acetyl-glucosamine, UDP-N-acetyl-galactosamine, UDP-glucuronate, GDP-mannose and GDP=fucose. Cow's goat's and sheep's colostrum contained significant amounts of nucleotides, which increased in amount from the moment of parturition, to reach a maximum 24--48 h later. The nucleotide concentration decreased thereafter with advancing lactation. Cow's milk contained substantial amounts of orotic acid, which increased during lactation, whereas in goat's and sheep's milk no increase took place. The cytidine and adenosine derivatives in ruminants' milk did not change significantly during lactation. The UDP-glucose/UDP-galactose ratio was measured in ruminants' milk at different stages of lactation.

Acid-soluble nucleotides of human milk at different stages of lactation.

The acid-soluble ribonucleotides of human milk were measured by enzymic and ion-exchange chromatographic procedures at different stages of lactation. Human colostrum and milk contained CMP, AMP, GMP, UMP, GDP-mannose, UDP-N-acetyl-glucosamine, UDP-N-acetyl-galactosamine, UDP-glucose, UDP-galactose, UDP and other minor nucleotides. Cytidine and adenosine derivatives were present in relatively higher amounts than in milk from ruminant species. The nucleotide concentration decreased with advancing lactation. Human milk at 3 months of lactation contained about 10 mumol/100 ml nucleotides, which represented about 75% of the amount of nucleotides present in human colostrum. Human milk did not contain orotic acid. The UDP-glucose/UDP-galactose ratio was constant during lactation and was similar to that of milks from ruminant species.

Metabolic changes induced by urethane-anesthesia in rats.

1. Fasting hyperglycemia was observed in urethane-anesthetized rats. No significant changes had been observed in fed animals. The effect is dose-dependent, being ineffective doses lesser than 1.4 g/kg of body weight. 2. Urethane originates a rise in glycemia during the first 10 min of anesthesia followed by control values at 30 min, and a latter hyperglycemic phase for more than 60 min that remain at 2 hr. 3. The negative correlationship between plasma glucose, lactate and amino acid levels suggest that gluconeogenesis may be the main responsibility of the observed hyperglycemia during the first phase, but it is possible that during the second phase a decrease in the consumption of glucose may take place as a consequence of the competitive effects of ketone bodies increased during the first 30 min of anesthesia. 4. We postulate that the mechanism of the hyperglycemic response to urethane is a sympathetic response with release of catecholamines both in the liver and in the adrenal gland which enhances gluconeogenesis and lipolysis.

Role of renal gluconeogenesis in the maintenance of glycaemia after L-tryptophan administration to rats.

The time-course of liver and kidney gluconeogenesis after L-tryptophan administration has been studied. Two and half hours after injection of L-tryptophan (0.5 g/kg body wt) a 97% inhibition of hepatic gluconeogenesis in starved rats was observed. Twelve hours later, the inhibition remained 35%. Hepatic glycogen was almost completely depleted (97%) in fed rats after 5 hours. At this time there was a severe hypoglycaemia in fed and 48 h starved rats which gradually disappeared with time, the values going back to normal after 12 hours. Tryptophan treatment was associated with a significant increase in renal gluconeogenesis in fed and 48 h starved rats with a maximum at 5 h (165% and 190% respectively). When hepatic gluconeogenesis was constantly inhibited in fed rats by periodic injection (every 4 h) of L-tryptophan, renal gluconeogenic ability remained increased throughout the experiment while blood glucose concentrations did not change. These observations suggest that kidney contributes to maintain glycaemic homeostasis under these conditions of liver gluconeogenesis impairment.

Stimulation of phosphoenolpyruvate carboxykinase (guanosine triphosphate) activity by low concentrations of circulating glucose in perfused rat liver.

1. After nicotinic acid treatment, rat liver glycogen is depleted and phosphoenolpyruvate carboxykinase activity increased, to about twice the initial value. 2. The increase in phosphoenolpyruvate carboxykinase activity promoted by nicotinic acid is prevented by cycloheximide or actinomycin D, suggesting that this effect is produced by synthesis of the enzyme de novo. 3. Despite the enhancement of phosphoenolpyruvate carboxykinase activity and glycogen depletion, which occurs 5h after the injection of nicotinic acid, the gluconeogenic capacity of liver is low and considerably less than the values found in rats starved for 48h. 4. When the livers of well-fed rats are perfused in the presence of low concentrations of glucose, the activity of phosphoenolpyruvate carboxykinase significantly increases compared with the control. 5. This increase is not related to the glycogen content, but seems to be also the result of synthesis of the enzyme de novo, since this effect is counteracted by previous treatment with cycloheximide or actinomycin D. 6. Phosphoenolpyruvate carboxykinase activity is not increased in the presence of low concentrations of circulating glucose when 40 mM-imidazole (an activator of phosphodiesterase) is added to the perfusion medium. 7. Addition of dibutyryl cyclic AMP to the perfusion medium results in an increase in phosphoenolpyruvate carboxykinase activity, in spite of the presence of normal concentrations of circulating glucose. On the other hand, the concentration of cyclic AMP in the liver increases when that of glucose in the medium is low. 8. These results suggest that, in the absence of hormonal factors, the regulation of phosphoenolpyruvate carboxykinase can be accomplished by glucose itself, inadequate concentrations of it resulting in the induction of the enzyme. The mediator in this regulation, as in hormonal regulation, seems to be cyclic AMP.

Induction of rat kidney gluconeogenesis during acute liver intoxication by carbon tetrachloride.

1. Glucose production from L-lactate was completely inhibited 24h after carbon tetrachloride treatment in liver from 48h-starved rats. The activities of phosphoenolpyruvate carboxykinase, fructose diphosphatase and glucose 6-phosphatase were decreased by this treatment in fed and starved rats, whereas lactate dehydrogenase activity was only decreased in fed animals. 2. The production of glucose by renal cortical slices from fed rats previously treated with carbon tetrachloride was enhanced when L-lactate, pyruvate and glutamine but not fructose were used as glucose precursors. Renal phosphoenolpyruvate carboxykinase activity was increased in this condition. 3. This increase was counteracted by cycloheximide or actinomycin D, suggesting that the effect was due to the synthesis de novo of the enzyme. 4. The pattern of hepatic gluconeogenic metabolites in treated animals was characterized by an increase in lactate, pyruvate, malate and citrate as well as a decrease in glucose 6-phosphate, suggesting an impairment of liver gluconeogenesis in vivo. 5. In contrast, the profile of renal metabolites suggested that gluconeogenesis was operative in the treated rats, as indicated by the marked increase in the content of phosphoenolpyruvate, 2-phosphoglycerate, 3-phosphoglycerate and glucose 6-phosphate. 6. It is postulated that renal gluconeogenesis could contribute to the maintenance of glycaemia in carbon tetrachloride-treated rats.

Pyruvate kinase activity and gluconeogenesis in rat liver after glycogen depletion with nicotinic acid.

Nicotinic acid administration, which depletes liver glycogen, leads to an increase of both pyruvate kinase L and phosphoenolypyruvate carboxykinase in liver by a factor of nearly two. The former is not prevented by either cycloheximide or actinomycin D. L-Cysteine, an allosteric inhibitor of pyruvate kinase L, favors gluconeogenesis from lactate in both nicotinic acid treated and starved animals.

Hormonal effects on the liver glucose metabolism in rainbow trout (Salmo gairdneri).

1. Glucagon, adrenaline and dibutyril cyclic AMP increased the release of glucose to the medium during incubation of liver slices from rainbow trout (Salmo gairdneri) while insulin had no effect. 2. Glycogen content decreased only slightly after cyclic AMP addition and even increased in the presence of glucagon and adrenaline. Consequently, the release of glucose was due mainly to gluconeogenesis. 3. This is corroborated by the reduction of glucose liberation in presence of alpha-cyanocinnamate, an inhibitor of gluconeogenesis.

[Stimulation of gluconeogenic capacity in partially hepatectomized rats (author's transl)]. / Estimulación de la capacidad gluconeogénica renal en ratas parcialmente hepatectomizadas.

Renal gluconeogenic capacity was enhanced to 150% 24 h after partial hepatectomy, remained increased at 48 h (144%) and returned to normal values at 72 h. Glucose production by renal cortical slices from hepatectomized rats was also enhanced 48 h after surgery when pyruvate, alpha-ketoglutarate and fructose were used as gluconeogenic precursors. The stimulation of renal gluconeogenic capacity seems to be due to the increase of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase activities which behaved similarly to glucose production after hepatectomy. The renal metabolic response may be partially due to starvation in the first 24 h. Afterwards food intake became normalized and the acceleration of glucose production should be attributed to hepatectomy. Since there was no metabolic acidosis in our experimental conditions the involvement of glucocorticoids in the stimulation of renal phosphoenolpyruvate carboxykinase and glucose-6-phosphatase activities is suggested.

Evolution of gluconeogenic enzyme activities during starvation in liver and kidney of the rainbow trout (Salmo gairdneri).

1. There was a general increase in the activities of enzymes involved in gluconeogenesis in liver and kidney of rainbow trout, Salmo gairdneri, during the second month of starvation. 2. The need of gluconeogenesis during the first month of the starvation period was probably minimal because of the utilization of liver glycogen as a source of blood glucose. 3. The decline of fat was more pronounced than that of protein total content in absolute values, suggesting that lipid reserved were the main sources of energy during starvation.