Simon Koletsky

Obese spontaneously hypertensive rats—A model for study of atherosclerosis

Abstract Probably as the result of a mutation a new type of spontaneously hypertensive rat has been obtained which, in addition to elevated blood pressure, exhibits genetic obesity, endogenous hyperlipemia, endocrine gland malfunction and metabolic abnormalities and develops premature atherosclerosis. The animals also show marked and persistent albuminuria which appears at an early age and is often associated later in life with a progressive nephrosclerosis which leads to azotemia or uremia. The animals have been designated as obese spontaneously hypertensive rats. They may provide a useful model to explore the relation of endocrine and metabolic abnormality to obesity and also for investigating the pathogenesis of atherosclerosis, especially in regard to the roles of high blood pressure and hyperlipemia. In addition the animal may also be of value in the study of human type 4 hyperlipoproteinemia of which it appears to be an experimental analog.

Lack of increased renin-angiotensin activity in rats with spontaneous hypertension.

Summary Three parameters of renin angiotensin activity were studied in rats with spontaneous hypertension. The juxtaglomerular index of these animals in the prehypertensive, early hypertensive, and chronic stage of the high blood pressure was significantly lower than in normal rats. Bioassays of renal vein blood for a pressor agent were consistently negative in hypertensive rats 6 weeks to 12 months of age, including tests performed in animals 6–8 weeks old when the blood pressure was rising to hypertensive levels. The renal vein plasma renin activity was within normal limits except for rats with longstanding high blood pressure which showed a significant reduction in activity. The findings indicate that neither the development nor maintenance of the high blood pressure in animals with spontaneous hypertension is due to increased activity of the renin-angiotensin system.

Rapid acceleration of atherosclerosis in hypertensive rats on high fat diet

Abstract Rats with unilateral renal hypertension were placed on a diet containing 40% fat in the form of egg yolk. In striking contrast to normotensive control rats, these animals rapidly developed a severe grade of atherosclerosis. Gross atherosclerosis of the mesenteric arteries was sometimes visible as early as 2 weeks after ingestion of fat was started. Coronary atherosclerosis was usually present within 1 or 2 months and was characterized by well developed atheromatous plaques, reactive cellular proliferation, and superimposed thrombosis. The rapid acceleration of atherosclerosis was attributed to the vascular damage caused by high blood pressure mainly prior to initiating the high fat diet. This damage apparently resulted in a greater propensity on the part of smooth muscle cells to accumulate lipid particles and in enhanced reactive hyperplasia of these cells on exposure to excess lipids. Another likely effect of the high blood pressure was to increase the permeability of the arterial intima to the passage of lipids.

Content and distribution of glycogen in Schistosoma mansoni.

Summary From 13.6 to 29.0% of the dry matter of the males of S. mansoni consisted of glycogen. In females the amount varied between 2.7 and 5.0%. The glycogen in both male and female worms was deposited principally in the musculature and parenchyma. The relatively small amount in the female is explained by the less well-developed musculature and parenchyma and the more abundant sexual apparatus which is glycogen negative. Histological studies were in general accord with the quantitative observation that the amount of glycogen in the male tends to increase with age.

Vasopressor Material in Experimental Renal Hypertension

Transfer of blood from rats with acute renal hypertension to normal recipient rats demonstrated that a vasopressor substance was present in the circulation of the hypertensive animals. This is consistent with the view that a humoral mechanism plays a role in the origin of the hypertension. In contrast to the acute stage, no vasoactive material could be demonstrated in the blood after the second week of hypertension. Either the amount of pressor substance was too small to detect or none was being produced. In the latter case, chronic renal hypertension cannot be attributed to a humoral mechanism.

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

Summary 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.

Pathogenesis of experimental hypertension induced by salt

Abstract 1. 1. Chronic salt ingestion in the rat often yields hypertensive cardiovascular renal disease. 2. 2. The natural history of this disease resembles that of essential hypertension in man. Morphologically, however, neither the vascular lesions nor the renal disease which accompany hypertension in the two species are strictly comparable. 3. 3. In the rat, salt loading and renal ablation are synergistic in producing hypertensive vascular disease. The reason for this is not clear, although it may relate to defective sodium metabolism. 4. 4. Altered electrolyte status in the peripheral vascular bed may play a role in the genesis of rat hypertension.

Relation of Renal Arterial Pressure to Activity of Renin-Angiotensin System in Renal Hypertension.

Summary Unilateral renal hypertension was produced in rats by constricting the aorta just above the ostium of the left renal artery. This caused a sharp reduction in renal arterial pressure which usually remained below 80 mm Hg for 1 to 2 weeks. During this interval the renal vein blood contained a potent vasopres-sor agent and an elevated content of renin. By 2 weeks the left renal arterial pressure had returned to normal levels in most animals and this was associated with disappearance of the vasopressor agent from renal vein blood as well as a marked reduction in the output of renin. Not a single rat was encountered in which a low renal arterial pressure persisted indefinitely or in which the kidney continued to produce excess vasopressor material or to discharge an increased amount of renin. These findings indicate that(1) in unilateral renal hypertension the renal arterial pressure probably governs the release of renin by the kidney and that(2) low renal arterial pressure and hence increased activity of the renin-angiotensin system are limited to the early or acute stage of renal hypertension.

Role of a Pressor Substance in Unilateral Renal Hypertension.

Summary Unilateral renal hypertension was produced by constricting the aorta of the rat between the ostia of the main renal arteries. The acute stage of hypertension probably depended on a renal humoral mechanism since during the first 2 or 3 weeks of the hypertensive state, blood from the renal vein of the ischemic left kidney contained a potent vasoconstrictor substance, probably angiotensin, which was also present in arterial blood but not in renal vein blood from the untouched right kidney. After 3 weeks the left kidney ceased to release a pressor agent and in addition no such agent was demonstrable in the general circulation by bioassay. Hence the chronic stage of unilateral renal hypertension could not be attributed to the direct vasoconstructive effect of a humoral pressor agent.

Reduction of atherosclerotic disease in genetically obese rats by low calorie diet.

Abstract Starting at 3 months of age genetically obese rats were maintained on a low calorie diet of Purina chow for the rest of life. On ad libitum diet of Purina chow such animals exhibit endogenous hyperlipidemia and spontaneous hypertension and frequently develop atherosclerotic vascular disease. The low calorie regimen was well tolerated by the obese rats and proved to be highly beneficial. It diminished the obese state, almost eliminated the hypertriglyceridemia, reduced the hypercholesterolemia, and substantially lowered the incidence of atherosclerotic lesions, i.e., to 14% as compared to 48% among obese rats on ad libitum diet. Since the animals had persistent hypertension in spite of the low calorie diet, it appears likely that control of the hyperlipidemia played a significantly role in the prevention of vascular disease.