Atherosclerosis following balloon catheter injury to the carotid artery and the aorta of hypertensive rats with normolipidemia or hyperlipidemia.

The carotid artery and abdominal aorta of hypertensive normocholesterolemic rats responded in similar manner to balloon denuding of the endothelium. One denuding resulted in an intimal fibrous plaque, while multiple such injuries increased the lipid content of the plaque and so yielded fatty-fibrous plaques, which perhaps represent an intermediate stage of atherosclerosis. In no instance did a single or multiple denuding lead to advanced atherosclerosis. Although the abdominal aorta of animals with one or with repeated denudings accumulated more lipid when placed on atherogenic died, the lesions remained essentially in the fatty-fibrous plaque category. Typical atherosclerosis was observed only occasionally and was limited to rats with multiple denudings. In rats with denuded carotid artery on an atherogenic diet classic atherosclerosis developed, especially when there were multiple episodes of injury. This was the first time the authors observed advanced atherosclerosis in the rat, and the lesions were quite comparable to human atherosclerosis. For the rat in this instance the principal factors in pathogenesis were hyperlipidemia and the repeated endothelial denudings, which promoted lipid deposit in the intimal plaques of the vessel.

Regression of atherosclerotic plaques in rhesus monkeys. Angiographic, morphologic, and angiochemical changes.

On a diet with high levels of cholesterol and sucrose, a beta-lipoproteinemia developed in rhesus monkeys that is similar to type II human hyperlipidemia. Lesion regression appeared in response to drastic lowering of serum cholesterol (SC) levels. This experiment analyzed angiochemical responses on the addition of a bile-acid sequestrant to continued atherogenic feeding, which resulted in ranges of moderate cholesterolemia that mimick those that occur in man. After two years of atherogenic diet, fatty fibrous plaques were demonstrated in ten monkeys; then cholestyramine resin, 1.5 g/100 g of the atherosclerotic diet, was added to the food of eight monkeys, whereas two served as controls during a 12-month regression period. Six adult control monkeys that did not receive the atherosclerotic diet were also killed. Seven experimental animals overall showed plaque regression when SC level fell from 400 +/- 130 to 237 +/- 74 mg/dL; one animal showed angiographic combinations of progression and regression. Angiochemical evaluation demonstrated discordant data with instances of decreased plaque cholesterol content and increased levels of collagen. On the average, plaque regression and final composition were related to absolute levels of SC reduction induced by cholestyramine. Regression required that the threshold levels of cholesterol be below 200 mg/dL. Plaques regressed mainly by lipid absorption; in this experiment and, in particular, arterial segments, collagen content sometimes increased.

Arterial wall renin and renal venous renin in the hypertensive rat.

1. Infusion of sufficient renin to raise the blood pressure of normal rats to hypertensive levels resulted in increased renin in the arterial wall. 2. Arterial wall renin and renal venous renin were normal in younger spontaneously hypertensive rats, but in older spontaneously hypertensive rats arterial wall renin was significantly increased and renal venous renin was significantly decreased. 3. Arterial wall renin in rats with either acute or chronic two-kidney Goldblatt renal hypertension was significantly increased, whereas circulatory renin was elevated in the former, but depressed in the latter. 4. Arterial wall renin may play a role in the maintenance of acute and chronic renal hypertension and also perhaps of spontaneous hypertension of long duration in older rats.

Failure of regression of atherosclerosis in dogs with moderate cholesterolemia.

Controversy exists as to whether regression occurs in atherosclerotic plaques in response to serum cholesterol reduction. In the present study, using sequential observation of canine atherosclerosis, we attempted regression in hypothyroid dogs. Animals with established lesions prior to a regression attempt were placed on a 0.05% cholesterol diet and observed up to 60 months. Weighted average cholesterols ranged from 235 to 587 mg/100 ml during the regression attempt. A control fed for the entire period of the experiment, 75 months, had an average weighted cholesterol of 435 mg/100 ml. We failed to obtain regression of atherosclerotic plaques in spite of reduction of serum cholesterol from high to moderate levels. The lesions in the experimental animals contained less lipid and more collagen and calcium than occurred in the control. Complicated plaques with aneurysm formation, stenosis of the distal aorta, and gangrene of the tail were also noted.

Effect of caloric restriction on basal insulin levels and the in vivo lipogenesis and glycogen synthesis from glucose in the Koletsky obese rat.

Fasting plasma immunoreactive insulin levels increased with age in hyperinsulinemic Koletsky obese rats, being almost four times as high as in lean siblings at 3 mo (40 +/- 5 muU/ml) and rising steadily to 82 +/- 4 muU/ml at 6 mo (about seven times higher than lean siblings). Restricting the food intake of the obese rats markedly reduced but did not normalize the hyperinsulinemia, which in these rats was accompanied by normal plasma glucose concentrations. The incorporation in vivo of D-U-14C-glucose into tissue lipids and glycogen was measured 1 hr after the intravenous injection of 1 g glucose (containing 100 muDi D-U-14C-glucose) per kg body weight in obese rats eating ad libitum, obese rats after 3 mo on a restricted food intake, and lean siblings. All tissues (heart, diaphragm, skeletal muscle, and adipose tissues and liver) of obese rats exhibited a significantly greater lipogenesis from glucose than those of lean siblings. Dietary restriction of the obese rats reduced the 14C incorporation into lipid to levels not significantly different from lean controls in all tissues except skeletal muscle and liver, where, although greatly reduced, lipogenesis was still significantly higher than in lean rats. Glycogen synthesis tended to be greater in all tissues of obese rats than in lean animals. Dietary restriction of obese rats did not greatly affect glycogen synthesis.

Simultaneous determination of plasma aldosterone, corticosterone, 11-deoxycorticosterone, 18-hydroxydeoxycorticosterone, cortisol, and 11-deoxycortisol. Methods and applications.

A method for the simultaneous determination of aldosterone, corticosterone (B), 11-deoxycorticosterone (DOC), 18-hydroxy-11-deoxycorticosterone (18-OH-DOC), cortisol, and 11-deoxycortisol in a single 1-ml sample of plasma is described. The method is applicable to both man and experimental animal. After extraction and purification by thin-layer chromatography (TLC), aldosterone was determined by radioimmunoassay (RIA) employing antibodies to aldosterone: B, DOC, cortisol and 11-deoxycortisol were determined by RIA employing antibodies to corticosterone; 18-OH-DOC was obtained colorimetrically using the Porter-Silber reagent. Recoveries after extraction and chromatography were: aldosterone 71% +/- 9.4 SD; B 81% +/- 10.2; DOC 73% +/- 8.4; cortisol 65% +/- 7.2; 11-deoxycortisol 74% +/- 6.3 using labeled steroids; 18-OH-DOC 82% +/- 8.7 using inert steroid. The method has a high specificity and is reproducible and accurate.

Effect of low calorie diet on the hyperlipidemia, hypertension, and life span of genetically obese rats.

A new strain of genetically obese rat recently obtained in our laboratory exhibits endogenous hyperlipidemia (marked hypertriglyceridemia and moderate hypercholesterolemia) and spontaneous hypertension. The animals die prematurely from kidney failure or from the complications of atherosclerosis. A low calorie diet proved to be highly beneficial to these rats. Body weight declined, obesity diminished, the hypertriglyceridemia was almost eliminated, and the hypercholesterolemia was reduced. However, the hypertensive state was not alleviated. Since the life span of the rats was greatly prolonged by a low calorie diet, the latter undoubtedly served to prevent or arrest the development of renal and vascular disease in these obese animals.

Pathologic findings and laboratory data in a new strain of obese hypertensive rats.

A new strain of rat characterized by genetic obesity, endogenous hyperlipidemia, and hypertension was obtained in this laboratory. The abnormal phenotype is inherited as a homozygous recessive trait. The animals exhibit marked hypertriglyceridemia, moderate hypercholesterolemia, and an electrophoretic pattern resembling that of human Type IV hyperlipoproteinemia. The average life-span is less than 1 year, due largely to the development of premature renal and vascular disease. The kidney lesion has both glomerulonephritic and nephrosclerotic components and is accompanied by marked proteinuria. About 12% of animals develop urinary tract calculi. The vascular disease consists of fibrous and fatty-fibrous intimal plaques, and polyarteritis. The obese animal offers a useful model for investigating abnormal lipid metabolism and the etiology and pathogenesis of atherosclerosis.