HC Rats Research Articles

Insulin and glucose suppress hepatic glycogenolysis by distinct enzymatic mechanisms

Both insulin and hyperglycemia can effectively suppress hepatic glucose output (HGO). We examined whether insulin and hyperglycemia specifically suppress liver net glycogen breakdown in a rat model in which glycogen is the major source of HGO. We further examined whether insulin and hyperglycemia act by similar or distinct enzymatic mechanisms. HGO, the rate of net glycogen loss, and glycogen phosphorylase and synthase activities were measured in fed, anesthetized rats infused with saline or insulin (7 mU/min/kg) while either maintaining plasma glucose at basal (7.8 ± 0.2 mmol/L, euglycemic clamp [EC]) or at 10 mmol/L above basal (18 ± 0.4 mmol/L, hyperglycemic clamp [HC]). During the basal period, the rate of HGO in each group was comparable to the rate of net glycogen breakdown, averaging 76 ± 9 and 75 ± 5 μmol/min/kg, respectively. Thus glycogen breakdown appeared to be a major source of ongoing HGO. Over the last 60 minutes of the experimental period, the rate of glycogenolysis averaged 69 ± 8 μmol/min/kg in saline-treated rats; this could account for about 80% of the total HGO. During both EC and HC studies, HGO was suppressed (5.5 ± 3 and −3.6 ± 10 μmol/min/kg, respectively; P < .001 for each). Net glycogen breakdown decreased by 50% in EC rats ( P < .05) and ceased in HC rats ( P < .001). Glycogen synthase was predominantly in the active form in all three experimental groups (87% ± 2%, 89% ± 2%, and 95% ± 3% in saline, EC, and HC rats, respectively). The fraction of glycogen phosphorylase in the active form was similar in saline (41% ± 2%) and EC (40% ± 2%) rats, but lower (23% ± 5%, P < .03) in HC rats. In summary, insulin fully suppresses HGO and partially inhibits net glycogenolysis in vivo without affecting the phosphorylation state of glycogen phosphorylase. Addition of hyperglycemia enhances phosphorylase a to b conversion and fully suppresses net glycogenolysis. Glucose produced by residual glycogenolysis during EC does not reach the systemic circulation and must be disposed of glycolytically in liver.

Self-selecting albino rats exhibit differential preferences for pure macronutrient diets: Characterization of three subpopulations

Analyses of natural feeding behavior in albino male Sprague-Dawley rats demonstrate that, when allowed to self-select from pure macronutrient diets (protein, carbohydrate and fat), these rats of the same genetic strain can be categorized into 3 subpopulations according to either their 24-h or their 12-h nocturnal patterns of nutrient intake. A majority of the animals (HC for high carbohydrate, 50% of the total population) consumed a diet rich in carbohydrate relative to protein or fat, while a smaller population of rats (HF, 30%) preferred the fat diet, and an even smaller population (HP, 20%) chose a high-protein diet. These 3 subpopulations, after a few weeks of maintenance on the diets, differed in their body weight, with the HF rats having a higher body weight than the HP animals, who tended to weigh more than the lightest HC rats. Whereas all subgroups exhibited a similar bimodal distribution of feeding during the nocturnal cycle, with peaks during the early and late dark periods, they were distinguishable on the basis of their nutrient consumption during specific phases of the dark cycle. This difference was most apparent in the early dark phase, when the 3 subgroups exhibited exaggerated preferences for the specific nutrient that was generally preferred over the 24-h cycle. This is in contrast to the middle dark phase, when diet preferences were attenuated or lost, and the late dark phase, when most rats were similar in showing an increased preference for protein and fat and a decreased preference for carbohydrate. The HF group was further distinguished by an unusually strong burst of feeding during the first 2 h of the dark period and an extra peak of feeding in the middle dark period (7th h), both of which were relatively high in fat content.

Increased transport of theophylline into gastrointestinal lumen and gastrointestinal dialysis by activated charcoal in rats with hepatic cirrhosis.

The characteristics of exsorption and/or excretion of theophylline into the small intestinal lumen in rats with hepatic cirrhosis (HC rats) induced by carbon tetrachloride were investigated by an in situ single-pass perfusion technique. The serum concentrations of theophylline after i.v. administration of aminophylline (10 mg/kg) in the HC rats were significantly higher than those in normal rats during the experimental period. Moreover, the exsorption of theophylline from blood into the intestinal lumen was significantly increased in the HC rats compared with the normal rats. Treatments with oral activated charcoal reduced the serum theophylline levels in the HC rats. Consequently, gastrointestinal dialysis by oral administration of activated charcoal may be a useful method to remove poisonous drugs from the blood in patients with hepatic failure (including cirrhosis), which decreases the systemic clearance.

コレステロール食負荷ラットでの血管壁ＰＧＩ２および血小板ＴＸＡ２産生に及ぼす抗血小板剤の影響

The effects of antiplatelet agents on the disorders of lipid and arachidonic acid (AA) metabolism were studied in hypercholesteromic rats (HC). HC rats received an atherogenic diet (containing 2% cholesterol, 0.5% cholic acid, 10% lard, 5% cane sugar, 0.2% methylthiouracil, and 82.3% basal diet) for 6 weeks, 350, 000units/kg of vitamin D2, and also olieve oil (5ml/kg) for 4 days. Antiplatelet agents, OKY 046 and ONO 3144, were administered to HC rats (100mg/kg/day). After 6 weeks, plasma lipids were measured by conventional methods, and both TXA2 generation in the platelet and PGI2 generation in the isolated aorta were measured by RIA.The results were as follows: 1) Plasma cholesterol, triglyceride and β-lipoprotein were increased in HC rats. 2) Vascular UGI2 generation was decreased, and AA induced platelet TXA2 generation, and TXA2/PGI2 induced by collagen or AA were elevated in HC rats, while platelet TXA2 generation and TXA2/PGI2 were decreased in OKY and ONO treated HC rats, 3) Atherosclerotic changes in intima and media were observed in 5/12 HC rats, 1/6 OKY treated HC rats and none of 4 ONO treated HC rats.These results might suggest that vascular PGI2 generation was decreased and platelet TXA2 generation was increased in these experimental atherosclerotic rats, however the administration of antiplatelet agents OKY 046 and ONO 3144 seemed to prevent atherosclerosis through the repairment of AA metabolism.

The hippocampus, time and working memory

Rats were trained on a discrete trial working memory leverpress alternation task, following hippocampal lesions (HC), cortical control lesions (CC) or sham operations (SO). Each trial consisted of a forced information response, for which a randomly selected lever was presented followed by a free choice stage, when both levers were presented. The rats were rewarded for pressing the lever which had not been presented at the information stage. When the information response was not rewarded, all rats learnt the task equally well at IRIs of up to 12.75 sec. When the information response was rewarded, the HC rats showed impaired choice accuracy. The extent of this impairment depended on the IRI, being greatest at long IRIs, and least at short ones. Varying the number of leverpresses required to complete the information response affected choice accuracy equivalently in all groups: all rats chose significantly less accurately when only one leverpress was required than when ten leverpresses were required. There was no interaction between the lesion treatments and the information response requirements. It was concluded that both the length of the IRI and the occurrence of events during the IRI determine the extent of the hippocampal lesion-induced performance deficit in working memory tasks. It is proposed that hippocampal damage disrupts an intermediate-term, high-capacity memory buffer, but leaves both a residual short-term memory system and the long-term retention of associations unaffected. This proposal leads to the prediction that reference memory tasks should also be affected by hippocampal lesions when a delay is introduced between making a response and being rewarded for doing so.

Effects of bovine growth hormone on the retarded cerebral development induced by neonatal hydrocortisone intoxication.

In comparison with normal controls, hydrocortisone-intoxicated rats (HC rats) had smaller cerebra, lowered 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNPase) activity, and greatly reduced learning ability. The reduction in cerebral weight and DNA content was considered to be caused by a decrease in the number of proliferating glial cells, because the usual postnatal elevation of thymidine kinase (TK) activity was found to be suppressed in the cerebra from the HC rats. Electron microscopic observation of the pituitary gland revealed that the 5-day-old HC rat contained growth hormone (GH) secretory cells which were fully packed with GH granules, suggesting a disorder in the system which releases GH. In an attempt to promote cerebral development in the HC rats, we administered bovine GH (bGH) to some of the HC rats daily from the day of birth until weaning (HC + bGH rats). In the HC + bGH rats, the cerebral DNA was restored to normal levels and a concomitant increase in TK and CNPase activity was noted. Furthermore, in the brightness discrimination test, whereas the HC + bGH rats attained the learning ability of the normal controls after only 10 sessions, the HC rats were unable to reach an equivalent level even after 25 sessions.