Haruki Matsumura

Genetic studies on induced and spontaneous hypercholesterolemia in rats

Abstract Weanling Sprague-Dawley rats of both sexes were fed a high cholesterol diet for 7 days. They were then divided into groups of high responders or low responders according to their plasma cholesterol levels. By the above selection and repeated sibmating within high responders of the same generation, progeny of both sexes became progressively more susceptible to dietary hypercholesterolemia. These rats have tentatively been given the short name ExHC and have at present been bred to the F 10 generation. Some, but not all, male ExHC rats develop spontaneous hypercholesterolemia on a basal low cholesterol diet.

Serum and tissue lipids and glomerulonephritis in the spontaneously hypercholesterolemic (SHC) rat, with a note on the effects of gonadectomy

A spontaneously hypercholesterolemic male rat, found in the Sprague-Dawley strain, was mated with normocholesterolemic females of the same strain: the male offspring were hypercholesterolemic. By selecting rats according to their plasma cholesterol levels and repeated brother-sister mating, progeny became progressively more hypercholesterolemic--especially the males--when fed a basal low-cholesterol diet. These rats were tentatively given the short name of SHC and have at present been bred to the F14 generation. Hypercholesterolemia in male SHC rats proceeded in two stages: plasma cholesterol rose only slightly during the first stage up to the age of about 10 weeks and then increased progressively in the subsequent stage. Female SHC rats developed a high degree of hypercholesterolemia from the age of 10 months. SHC rats maintained on the basal diet were not obese, but their kidneys and livers enlarged. Histological examination showed that glomerulonephritis developed in the kidney of male SHC rats by the age of 9 months. The liver of these rats was not fatty and contained rather less lipid than usually found in the normal Sprague-Dawley rat. Male and female SHC rats were subjected to gonadectomy at the age of 4 weeks, and were then maintained on the basal diet for 18 weeks. Blood cholesterol was higher throughout the experiment in ovariectomized female SHC rats than in controls, and the renal lesion was correspondingly worse. However, gonadectomy in male SHC rats had no effect on the disease.

INDUCTION OF AORTIC LIPID DEPOSITION IN A HIGH-RESPONSE (ExHC) RAT FED A DIET CONTAINING CHOLESTEROL AND CHOLIC ACID

Male ExHC and Sprague--Dawley rats were fed a diet containing 3% cholesterol, 0.6% sodium cholate and 15% olive oil for 16 weeks. The ExHC rat is highly susceptible to dietary hypercholesterolemia. Aortas of the ExHC rats showed Sudan-stained deposits and cholesterol accumulation in the intima and media, whereas no deposited lipids were seen in those of the Sprague--Dawley rats. In male and female ExHC rats fed diets containing the above supplements at 3 dose levels, plasma cholesterol and aortic lipid deposition were found to be dose-dependent. Lipid deposition was more prominent in female than in males, but aortic intimal proliferation was absent.

Increase of serum high density lipoprotein with progression and regression of aortic lipid deposition in rats

The progression and regression of aortic lipid deposition was studied in male ExHC rats. Rats in the progression group were fed an atherogenic diet containing 2% cholesterol, 0.4% sodium cholate and 10% olive oil for periods up to 32 weeks. Rats in the regression group were first fed the atherogenic diet for 16 weeks, and then maintained on a basal low cholesterol diet. Half the rats were killed at 4 weeks and the other half at 16 weeks after cessation of the atherogenic diet. Rat aortas of the progression group contained progressively more lipid pari passu with the duration of cholesterol feeding, but connective-tissue proliferation was absent. Deposited lipid in the aorta of cholesterol-fed rats disappeared very slowly after the rats were returned to the basal diet. serum HDL decreased in the hypercholesterolemic ExHC rats fed the atherogenic diet for 4 weeks. By contrast, serum HDL and apo A-I increased in both hypercholesterolemic ExHC rats fed the atherogenic diet for 32 weeks and slightly hypercholesterolemic ExHC rats fed the basal diet for 16 weeks in the regression period.

Biological studies of AT-308: Part 2. Hypocholesterolemic effect of AT-308, a new derivative of 1,2,4-oxadiazole, in rats

Abstract The hypocholesterolemic effect of a new 1,2,4-oxadiazole derivative, AT-308, was studied in rats fed a basal or high cholesterol diet. AT-308 significantly decreased the plasma cholesterol level in both spontaneously and dietetically hypercholesterole mic rats at a daily dose of 100 mg/kg. It had little or no effect on plasma triglycerides and phospholipids, or on liver lipids.