Comparative atherogenic effects of cholesterol and cholesterol oxides.

Previous findings indicating that the oxidation products of cholesterol are associated with atherogenicity have led to a comparative study of the subchronic effects of feeding rabbits purified cholesterol, oxidized cholesterols free of cholesterol and cholesterol esters, or a mixture of cholesterol and oxidized cholesterols. Macroscopically, the cholesterol-fed animals exhibited 6-fold more arterial lesions than the animals fed cholesterol-free oxidized cholesterols. Microscopically, there was no statistically significant difference from the control in the number of histochemically-defined lesions in any of the groups. However, the lesions in the cholesterol-fed group were more severe, as indicated by a statistically significant increase in the magnitude of the lesions. This increased severity was also characterized by greater frequency and intensity of Azure A/Thionin, VonKossa, and Horseradish Peroxidase-Wheat Germ Agglutinin staining. Electron-microscopic studies of normal appearing arterial tissues showed an increased density of viable smooth muscle cells and an increase in vacuolar extracellular debris in the cholesterol-fed group. Oxidized cholesterols in the concentrations and relative compositions administered here are markedly less atherogenic to rabbits than highly purified cholesterol.

The influence of dietary unsaturated cis and trans and saturated fatty acids on tissue lipids of swine.

A feeding trial was conducted to evaluate the effects of dietary trans unsaturated fatty acids (trans fat) and of the interplay of dietary saturated fatty acids (saturated fat), cis unsaturated fatty acids, (cis fat) and trans fat on tissue lipids, particularly those effects suggestive of angiotoxicity. Swine were fed for 10 months a diet containing 17% added fat. Seven blends of varying proportions of the 3 fat components provided sufficient sample points to permit an examination of the interplay. Parameters under study included weight gain, serum cholesterol and triglyceride concentrations, lipoprotein lipid profile, total lipid and cholesterol concentrations of liver, heart and aorta, fatty acid composition of liver and aorta lipids and hepatic fatty acid synthesis and cholesterol synthesis and oxidation. Fat blends containing disproportionately high levels of saturated or cis fat generally elicited responses consistent with results reported by others. The notable exception was the serum cholesterol concentration. Throughout the study, the swine were hypercholesterolemic. Swine fed the high saturated fat blend had serum cholesterol levels equal to those swine fed the high cis fat blend. Serum cholesterol levels in the swine fed the other fat blends were more elevated. Another apparent anomaly was the lower concentration of lipid in the aortas of swine fed the high-saturated fat diet. The impact of the trans fat was modulated by the relative proportions of saturated and cis fat in the diet. The impact of trans fat was of greater magnitude for most parameters when the fat blend was low in saturated fat. The sole parameter suggestive of trans fat-mediated angiotoxicity was the distribution of lipids in lipoprotein fractions. Swine fed diets containing trans fat had lower relative proportions of the alpha-lipoprotein lipids. Although hypercholesterolemic, the high fat diets were not overtly angiotoxic except when fed to swine that carried a specific immunogenetically-defined low density lipoprotein.

Effects of dietary 3-methylthiopropionate on metabolism, growth and hematopoiesis in the rat.

Rats were fed a basal diet supplemented with (2.57%) 3-methylthiopropionate (MTP) for 2 weeks. A marked depression in growth and food intake similar to that found in rats fed an equimolar level of methionine was observed. While supplemental glycine or serine alleviated the toxicity due to dietary methionine, similar levels added to the diets of rats fed MTP were without effect. The spleens of rats fed diets containing 2.57% MTP were grossly enlarged and darkened in comparison to spleens from control rats and histological examination of these spleens by light and transmission electron microscopy (TEM) revealed sequestration of large numbers of erythrocytes in the splenic sinusoids and red pulp similar to that seen in rats fed high levels of methionine. Marrow changes included increased numbers of erythroblastic islets and subtantial electron dense hemosiderin deposits in islet reticulum cells. Examination of peripheral blood erythrocytes by scanning electron microscopy revealed extensive variation in the size of the erythrocytes and the presence of large numbers of misshapen red cells in rats fed the diets containing MT. When viewed by TEM many erythrocytes had obvious membrane defects and remnants of cytoplasmic organellae. Many erythrocytes with reticulocyte morphology were present in the peripheral blood. This condition is characteristic of maturation arrest at the reticulocyte stage of development. The similarity of depression in growth and food intake and the identical abnormalities found in the spleens of rats fed high levels of MTP and methionine suggest that the transamination pathway of methionine catabolism may be important with respect to the toxicity of methionine. The ultrastructural changes noted in MTP-fed rats suggest a serious dysfunction of red cell hematopoiesis. The large numbers of defective and/or immature erythrocytes released from the marrow into the peripheral circulation, only to be later sequestered and destroyed in the spleen, is a reflection of a serious derangement.

Pathophysiology of dehydromonocrotaline-induced pulmonary fibrosis in the beagle.

The purpose of this study was to characterize the sequential hemodynamic alterations and pulmonary vascular lesions produced by a single pulmonary artery injection of the vasotoxic pyrrolic alkaloid dehydromonocrotaline in the young beagle. Normotensive pulmonary pressure was replaced by hypertension 21 days after injection. By 28 days, the pulmonary pressure and total pulmonary vascualr resistance of the experimental animals were significantly greater than the controls (p less than 0.01). Right ventricular work increased from a baseline mean of 0.58 to 1.40 kg . m/min. Morphological and morphometrical analyses revealed alveolar edema, increased numbers of alveolar macrophages, cellular hyperplasia in the alveolar septa, and a progressive interstitial fibrosis. The precise mechansims by which dehydromonocrotaline injection initiates and promotes pulmonary hypertension and pulmonary fibrosis still needs clarification; however, our data indicate that the fraction of air space is reduced relative to the fraction of tissue space, and this change occurs with concurrent fibrosis in the alveolar septa and an increased pulmonary arterial pressure although hypoxia was not clinically detectable.

Fibrin thrombosis in monocrotaline pyrrole-induced cor pulmonale in rats.

Investigations were carried out to determine the lung lesions responsible for the development of pulmonary heart disease, cor pulmonale, in rats treated with monocrotaline pyrrole or monocrotaline. Animals with right ventricular hypertrophy showed microscopic lung alterations consisting of alveolar edema; fibrin thrombi with partial to complete occlusion of arteries, arterioles, capillaries, and veins; connective tissue proliferation of alveolar septae; cellular hyperplasia of septae; and medial hypertrophy of arterioles. Due to the high incidence of fibrin thrombi in animals with right ventricular hypertrophy, we believe that formation of fibrin thrombi plays a decisive role in the development of chemically induced cor pulmonale.

Growth depression and tissue reaction to the consumption of excess dietary methionine and S-methyl-L-cysteine.

Similar depressions in growth were observed when rats consumed a 10% casein basal diet containing equal quantities of either methionine or S-methyl-L-cysteine. Supplemental glycine or serine partially alleviated the growth depression caused by the high levels of methionine but were ineffective in alleviating the growth depression caused by high levels of S-methylcysteine. Histological examination of five organs of rats fed the basal, high methionine or high S-methylcysteine diet for 6, 13 or 20 days revealed that only the spleens were affected in that there was erythrocyte engorgement and an accumulation of hemosiderin. The intensity of iron staining in spleens decreased from the second to the third week. The similarity in the depression of growth and splenic damage observed in rats consuming high levels of methionine or S-methylcysteine is consistent with an earlier suggestion that metabolism of the methionine or S-methylcysteine is consistent with an earlier suggestion that metabolism of the methyl group is in some way involved in the toxicity of methionine.

Protein overload nephropathy in rats with unilateral nephrectomy. A correlative light immunogluorescence and electron microscopical analysis.

We wish to determine what cellular and functional alterations are associated with the development of glomeruloscierosis when rats with one kidney are fed an excess of salt or protein. Rats with one kidney are more likely to develop pronteinuria and glomerulosclerosis than control animals. Blood pressure recordings indicate that proteinuria and glomerulosclerosis occur before hypertension is evident. Fluorescent antibody studies disclose that albumin accumulates in the epithelial cells of glomeruli and tubules. Ultrastructural examination shows that vacuolozation of epithelial cells and basement membrane thickening precede the sclerotic collapse of capillary loops. Increased concentrations of sodium or urea that are found in urines of these rats favor the point of view that an elevation of solute load when combined with a reduction of renal mass will on some unknown manner accelerate the deterioration of glomeruli.

Myocardial fibrosis and smooth muscle cell hyperplasia in coronary arteries of allylamine-fed rats.

Immature female Long-Evans rats were fed 2 g of allylamine-HCl kg of commercial diet for periods of 84-281 days. Coronary arteries and myocardium were examined in 16 control and 23 test rats. Cellular alterations in the arterial tributaries were found principally proximal to or within the areas of myocardial fibrosis. Whereas intimal smooth muscle cell (SMC) hyperplasia was prominent in vessels of smaller caliber, medial hyalinosis was seen frequently in arteries with diameters greater than 200 mu. Intimal hyperplasia developed in the peripheral coronary branches without any evidence of leukocytic infiltration or thrombus formation. It appeared that SMC hyperplasia in the intima contributed more often to a reduction of luminal patency than medial hyalinosis in allylamine-fed rats. On the basis of alterations in the coronary arteries and the localization of fibrosis, we believe that hypoxia is the cause of myocardial necrosis.