Effects of naproxen and methotrexate on the extent of aortic lesions and cholesterol concentrations in cholesterol-fed rabbits

Abstract

In this study rabbits were fed a hypercholesterolemic diet for 8 weeks with and without drug additives. Extent of aortic lesions was determined by planimetry and cholesterol concentrations by chemical analysis. Results in the naproxen-treated group were not significantly different from those in the untreated group. Methotrexate, a DNA synthesis inhibitor, resulted in significantly less extensive lesions and in lower aortic cholesterol concentrations. We have previously shown that two other compounds, hydroxyurea and mercaptopurine, that interfere with DNA synthesis have a similar beneficial effect. Aortic tissue cholesterol and extent of lesions were shown in this study (and previously) to be significantly correlated. Since drugs frequently have multiple metabolic effects these drugs might produce their effects on the lesion by retarding cholesterol accumulation in the aorta. However, it seems more likely that the effect was produced by retardation of proliferation of smooth muscle cells (either by preventing entry into the DNA synthesis phase or by death in the peridivision phase). The lower cholesterol accumulation in the aorta could be secondary perhaps because fewer cells were present that were susceptible to excessive cholesterol accumulation.