Marked hypercholesterolemia and moderate lipid infiltration of the aorta were induced by feeding rabbits a diet containing 1% cholesterol + 3% corn oil for 70 days. In the liver the concentration and pool size of cholesterol increased and those of triglycerides (TG) decreased. On dietary addition of vitamin A and vitamin E (44 000 I.U. and 125 mg respectively, once daily for 5 days a week) the following changes were noted in comparison with the fat-fed rabbits not receiving extra addition of vitamins. There was a slight decrease of the levels of plasma cholesterol and an increase of those of plasma TG. The liver cholesterol concentration increased but, according to the concomitant reduction of the liver weight, there was no significant change in lever cholesterol or TG pools. In the aorta the vitamins markedly reduced the lipid infiltrated area as well as the cholesterol content. Both niceritrol** and S-2040 [pyridine-2,5-dicarboxylic acid di(beta-pyridylcarbinol ester)] in a dietary concentration of 0.5% decreased plasma cholesterol by about 20%. This reduction, as well as that induced by the vitamins, was confined to the VLDL-fractions only. S-2040 slightly reduced the cholesterol accumulation in the aorta. In rabbits given both the vitamins and niceritrol or S-2042 there was an additive reduction of plasma cholesterol. Here the nicotinic acid derivatives were partly able to counteract the increases of plasma TG induced by the vitamins. In the aorta the combination vitamins + S-2042 but not that of vitamins + niceritrol tended to give a better protection than the vitamins alone. On a normal diet vitamins A + E significantly increased the liver cholesterol concentration and pool and decreased the liver TG pool, but did not affect the other parameters. Possible mechanisms for the prophylactic action of the vitamins against lipid infiltration of the aorta of cholesterol-fed rabbits are discussed.

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PubMedDate not supplied

A nicotinic acid ester and experimental atherosclerosis: no significant effect of treatment with niceritrol (pentaerythritoltetranicotinate) on cholesterol in aorta of rabbits previously fed with cholesterol-enriched diet.

The influence of niceritrol on cholesterol in serum, liver and inner aorta of 115 rabbits was studied during a period where a cholesterol-enriched diet was given and during two succeeding periods after which cholesterol addition to the diet was discontinued. Niceritrol given together with cholesterol for 6 weeks reduced significantly the concentration of cholesterol in serum and liver, but not in the inner aorta. During 16 weeks decrease of serum cholesterol after discontinuation of cholesterol feeding no significant effect of niceritrol was observed on the decrease in serum and liver cholesterol or on the concentration of cholesterol in inner aorta. When serum cholesterol had normalized 16 weeks after discontinuation of cholesterol feeding, addition of niceritrol to the diet for the following 16 weeks did not significantly affect the concentration of cholesterol in liver and inner aorta. Animals in all groups were injected intravenously with an equal amount of [3H] cholesterol 3 weeks before discontinuing cholesterol feeding. Niceritrol did not significantly affect the amount of accumulated labelled cholesterol in inner aorta. The present results indicated that niceritrol had no significant effects on metabolism of cholesterol in inner aorta of the hypercholesterolemic and previously hypercholesterolemic rabbits.

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PubMedDate not supplied

Distribution of cholesterol and triglycerides among lipoprotein fractions in fat-fed rabbits at different levels of serum cholesterol.

The serum lipoproteins of rabbits given semisynthetic cholesterol-free diets containing coconut oil or butter or a conventional rabbit chow supplemented with cholesterol, were studied by preparative ultracentrifugation and electrophoresis. (1) All three diets elevated the total cholesterol level but only the coconut oil diet markedly increased the triglyceride (TG) content in addition. All ultracentrifugation fractions showed elevated cholesterol/TG ratios, and this was especially evident for the cholesterol diet. In the hyperlipidemic rabbits cholesterol was therefore mainly transported in lipoproteins with a changed lipid composition. (2) The lipid levels of the "HDL" fraction were more or less unaffected by the lipid concentration in whole serum. In the total serum cholesterol ranges 150-500 (coconut oil diet) and 100-300 mg/100 ml (cholesterol diet), most cholesterol was transported as "LDL" cholesterol. This latter fraction reached maximum cholesterol concentrations of about 350 (coconut oil diet) and 400 mg/100 ml (cholesterol diet) at total cholesterol levels of approximately 600 and 1200 mg/100 ml serum, respectively. At still higher levels of total cholesterol, the whole increment was concentrated to the "VLDL" fraction. (3) With semisynthetic diets in the whole cholesterol range 250-400 mg/100 ml it was possible, with respect to cholesterol, to induce fairly similar concentrations and distributions to those seen in man, with about 60% transported as "LDL", 30% as "VLDL" and 10% as "HDL" cholesterol with the coconut oil diet and 65%, 20% and 15%, respectively, with the butter diet. Such experimental conditions seem to be suitable for testing the hypocholesterolemic action of drugs intended for human hyperlipidemia Type II. (4) Compared with earlier investigations on rabbits, the present distribution study suggests that the degree of aortic lipid infiltration in cholesterol-fed rabbits is better related to the levels of "LDL" than to "VLDL" cholesterol.

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PubMedDate not supplied

Glucocorticoids augment fibroblast-mediated contraction of collagen gels by inhibition of endogenous PGE production.

Glucocorticoids are currently regarded as the drug of choice in the treatment of inflammatory airway and lung diseases, however, they are not routinely effective in fibrotic phases of inflammation. In the current study, glucocorticoids were investigated for their ability to affect fibroblast mediated contraction of a three dimensional collagen gel, a measure of one aspect of tissue remodeling. Dexamethasone, budesonide, hydrocortisone and fluticasone propionate were all able to significantly augment fibroblast contractility in a concentration dependent manner. Glucocorticoids also had an augmentative effect on collagen gel contraction mediated by fibroblasts from bronchi, skin and bone marrow. The increased contractility was not due to cell proliferation or to collagen degradation, since the glucocorticoids did not alter the amounts of DNA and hydroxyproline in the gels. The concentration of prostaglandin E2 (PGE2) in supernatant media was lower from glucocorticoid-treated gels compared to control gels. Consistent with this, addition of exogenous PGE2 to the culture system restored the contractile properties and indomethacin augmented contraction similar to the glucocorticoids suggesting that inhibition of prostaglandins or related eicosanoids may be the mechanism by which the increased contractility occurs. DBcAMP, forskolin and the long lasting beta2-agonist formoterol were able to reverse the effect of the glucocorticoids on fibroblast mediated collagen gel contraction suggesting that enhancers of cAMP can counteract the effect of glucocorticoids. Thus, we provide evidence that glucocorticoids have the ability to directly augment fibroblast contractility by inhibiting fibroblast endogenous PGE synthesis. The findings could be one possible mechanism to explain the poor therapeutic response to glucocorticoids on the later stages of fibrotic diseases.

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