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Dietary sodium saccharin is associated with bladder tumors when fed at high levels to the male rat. Under these conditions urinary pH, sodium concentration, and volume are elevated and proliferative changes are present in the urothelium. Extensive epidemiological studies have shown that saccharin does not increase the risk of bladder cancer in humans and laboratory investigations have shown that sodium saccharin is not mutagenic and does not bind to DNA. Recent research indicates that the urothelium in male rats is damaged under conditions of high urinary pH and sodium levels by a mechanism that involves alpha 2u-globulin and possibly silicate crystalluria. These studies and their implications for human health risk are reviewed.

An unsaturated fatty acid preparation containing 90 to 95% linoleic acid was tested on cholesterol-induced hypercholesterolemia and atherosclerosis in the rabbit. The rabbits, treated with cholesterol dissolved in the unsaturated fatty acid, revealed a significantly higher hypercholesterolemia and more marked atherosclerosis than the rabbits that were treated with cholesterol dissolved in the same amount of olive oil.

The role of the regenerated adrenal gland in adrenal-regeneration hypertension has been explored in a series of experiments in the rat. Sensitization of the animals by unilateral nephrectomy and replacement of the drinking water by 1% saline were instituted at various intervals after unilateral adrenalectomy and contralateral adrenal enucleation. Comparisons were made of blood pressure, heart and kidney weight, and cardiovascular lesion in groups of rats sensitized at 0, [Formula: see text], 5 and [Formula: see text] weeks after adrenal enucleation. The results suggest an inverse relationship between the degree of adrenal regeneration present and the severity of the hypertension which developed following sensitization.

An experimental model (the scorbutic guinea pig) was utilized for studying the effect of conjugated equine estrogen (Premarin) on pathologic epiphysial bone formation. Fifty male guinea pigs were kept on an ascorbic acid-deficient diet, while another 50 were maintained on normal diet. Twenty-five guinea pigs in each group were also given 1 mg conjugated equine estrogen by gavage 3 times weekly. The estrogen exerted a marked protective effect against the epiphysial bone lesions of the experimental scurvy. This action is probably not specific. The significance of the findings is discussed in relationship to the general matabolism of bone.

The relationship between thyroid function and response to a synthetic adrenergic agent, isoproterenol, has been studied in the rat. Hypothyroidism after thyroidectomy or treatment with propylthiouracil for one or three weeks resulted in milder symptoms, reduced heart weights and less severe heart lesions after isoproterenol treatment than was seen in the controls. Thyroxine treatment on the other hand increased the mortality and heart weight after isoproterenol but had less marked effects on the myocardial necrosis. The myocardial infarct-like necrosis produced by isoproterenol is believed to be due to local ischemia resulting from a relative hypoxia in the myocardial fibres stimulated by this drug. The relationship seen between thyroid function and isoproterenol sensitivity supports this concept.

Rats were operated by unilateral nephrectomy, unilateral adrenalectomy and contralateral adrenal enucleation, they were then given saline to drink. During the process of adrenal regeneration a marked hypertension developed with cardiac and renal hypertrophy. Treatment of adrenal-regeneration hypertensive rats with Amphenone caused a reversal of blood pressure to normotensive limits and decreased the cardiac and renal hypertrophy. Amphenone treatment of rats started two weeks after adrenal-enucleation prevented the anticipated rise in blood pressure. These favourable effects on the blood pressure are accompanied by marked lipid accumulation in the regenerated adrenal gland affecting primarily the fasciculata zone. The administration of Amphenone to normal animals caused no depression in the blood pressure, nor did it affect the hypertension, cardiac hypertrophy, glomerular or arteriolar lesions of adrenalectomized rats given desoxycorticosterone acetate and saline.

SummaryTreatment of rats having adrenal-regeneration hypertension with propylthiouracil, results in decrease in body and tissue weights and marked lowering of hypertensive blood levels. This treatment also results in shrinking of width of the fasciculata zone in regenerated adrenal gland and a marked change in pituitary basophils. An increase in basophils of the pituitary has also been found in control rats with adrenal-regeneration hypertension.

I n 1958, during the course of some comparative toxicity studies, we observed’ that a synthetic adrenergic bronchodilator, which structurally resembled isoproterenol, caused massive myocardial necrosis in the rat. By testing isoproterenol (l-/3,4-dihydroxyphenyl/-2-isopropylamino ethanol HCl) in multiple dose levels, we developed a pharmacologic technique for producing in the rat an infarct-like myocardial necrosis of uniform severity2 which resembles closely human myocardial infarction. This observation has been confirmed by other groups who used this method for a model in studying the problems of experimental myocardial infarction.s-9 In subsequent experiments, in order to investigate the pathogenesis of the isoproterenol heart necrosis, we have studied several endogenous and exogenous factors which were thought to have an effect upon the development of this lesion. The results of some of these experiments have already been published. These will be reported only in summary form here and the reader can receive full information in the related papers. The effect of sex hormones and starvation on isoproterenol heart necrosis are original studies and will be described in detail.