In cholesterol-fed rabbits the extent of monocyte involvement in atherogenesis may be influenced by the level of circulating leukocytes during hypercholesterolemia. We characterized the leukocytosis in rabbits fed either a 0.25% or a 0.1% cholesterol-enriched diet (0.25% or 0.1% rabbits, respectively). Circulating leukocytes were elevated by 1 week of feeding, and the elevation was sustained for at least 30 weeks. Differential counts were unchanged. Immature leukocytes were not seen, indicating that the leukocytosis was not due to premature release of bone marrow cells. Animals were free of bacterial or parasitic disease; selected rabbits with leukocytosis had normal body temperatures. Spleen weights averaged at least 100% higher in 0.25% rabbits but did not show histological evidence for hematopoiesis that could account for the leukocytosis. At approximately 22 weeks there was a second rise in leukocytosis in bilirubinemic 0.25% rabbits, suggesting that in the late stages of hypercholesterolemia, leukocytosis is related to liver failure. Cholesterol-fed rabbits also showed thrombocytosis. Existing leukocytosis and hypercholesterolemia were reversed to pretreatment levels by switching the rabbits to chow diets. In bone marrow from 0.25% rabbits, the mean number of cells per gram was greater (p<0.05) than that from normocholesterolemic rabbits. In 0.25% rabbits, the fraction of blood mononuclear cells showing phagocytosis of immunoglobulin G-coated red blood cells did not differ from that of controls, suggesting an unchanged population of these cells with regard to Fc and phagocytic function during hypercholesterolemia. These data suggest an effect (direct or indirect) of hypercholesterolemia on the production of leukocytes in the bone marrow and/or on the circulation kinetics of leukocytes in the blood. (Arteriosclerosis and Thrombosis 1991;ll:985-994)
The synthesis and biological activities of biarylamide-substituted diaminoindanes as microsomal triglyceride transfer protein (MTP) inhibitors are described. One of the more potent compounds, 8aR, inhibited both the secretion of apoB from Hep G2 cells and the MTP-mediated transfer of triglycerides between synthetic acceptor and donor liposomes with IC(50) values of 0.7 and 70 nM, respectively. In normolipidemic rats and dogs, oral administration of 8aR dose-dependently reduced both plasma triglycerides and total cholesterol. Moreover, in rats and dogs, 8aR also prevented the postprandial rise in plasma triglycerides following a bolus administration of a fat load. Because MTP inhibitors decrease very low density lipoprotein assembly in the liver, the potential for hepatic lipid accumulation was evaluated. In normolipidemic rats, hepatic cholesterol and triglyceride contents were dose-dependently increased by 8aR. However, hepatic lipid accumulation resulted in negligible change in total liver weight and was reversible after withdrawal of the compound.
Endothelin-1 (ET-1) has been implicated in many chronic renal glomerular diseases. The purpose of this study was to investigate whether the levels of mRNA expression of endothelin-converting enzyme-1 (ECE-1) and endothelin-A- and -B- (ET(A) and ET(B)) receptors are altered during the progression of interstitial fibrosis following ureter ligation. Rats were subjected to left ureter ligation or a sham operation and euthanized 5 days afterward. Kidneys were fixed in Carnoy's fixative, embedded in paraffin, and sectioned for assessment of interstitial fibrosis by staining for collagen III using immunofluorescence techniques. The area occupied by collagen staining was quantified by image analysis. Kidneys from obstructed rats showed a 54% increase in the area occupied by collagen III staining compared to the contralateral kidney, and an 89% increase compared to sham-operated kidneys. The mRNA levels of ECE-1, as well as ET(A)- and ET(B)-receptors in the kidney were analyzed by Northern blots. It was found that the ECE-1 and ET(A)-receptor mRNA levels in kidneys subjected to ureter ligation increased by 92% and 71%, respectively, when compared with those obtained from the contralateral kidneys. In contrast, mRNA levels of ET(B)-receptors were not significantly different between the two groups. These results suggest that ET-1, through interaction with the ET(A)-receptors, may play a role in the progression of interstitial fibrosis following ureter ligation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.