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Objective: Endothelin (ET)-1 has proatherogenic properties, since ET receptor antagonists reduce atherosclerotic lesions in animals. However, we recently demonstrated that ET-1 and ETB receptors are increased in atherosclerotic lesions. To further examine the effects of ETB receptor antagonism on atherogenesis, we investigated the chronic effects of the nonselective ETA/ETB receptor antagonist SB209670 on the development of atherosclerosis in apolipoprotein E (ApoE)-deficient mice. Methods: Ninety-four male mice (10 weeks of age) were randomly divided into four groups: mice fed a Western-type diet or a chow diet with SB209670 treatment (10 mg/kg/day) or placebo for 12 weeks. Results: In mice fed the Western-type diet, but not in mice fed the chow diet, treatment with SB209670 significantly attenuated the increase in plasma total cholesterol, predominantly in the very-low-density lipoprotein and intermediate-density lipoprotein fractions, without altering the plasma triglyceride level. Furthermore, treatment with SB209670 significantly reduced the extent of aortic atherosclerosis, by 53% in mice fed the Western-type diet and by 38% in mice fed the chow diet. Histological analysis revealed that SB209670 prevented the formation of atheromatous plaque lesions by inhibiting the fibroproliferative process. Conclusion: We found that chronic administration of SB209670 reduced diet-induced hypercholesterolemia and atherosclerosis in ApoE-deficient mice. Thus, nonselective ET receptor antagonists may have a therapeutic potential in the treatment of human atherosclerotic disease.

Intimal infiltration of lipid-filled macrophages (Mφs) is an important event in the pathogenesis of atherosclerosis. To better understand Mφ functions, a model for the extravascular in vivo generation of foam cells in rat peritoneal cavities was utilized. Morphologic alterations, intracellular cholesterol accumulation, subpopulation, activation and proliferative properties of Mφs from hypercholesterolemic rats (HMφs) were compared with Mφs from normal rats (NMφs). HMφs revealed a significant increase of cholesterol mass in the cytoplasm; 65% of HMφs were loaded with various amounts of oil-red-O-stainable lipid droplets which were barely identified in NMφs. Ultrastructurally, accumulated lipid droplets in HMφs were either membrane-bound or membrane-free in the cytoplasm. Further biochemical analysis revealed that cellular levels of total cholesterol, free cholesterol, and cholesteryl esters in HMφs were increased 6-, 8-, and 4-fold, respectively. As to the Mφ subpopulation, there was a significant increase of Ia-antigen-positive cells in HMφs (15.8 vs. 8.8%), indicating that these cells were in a state of activation. To investigate the mitotic activity, the proliferative potential of Mφs was determined both in vivo and in vitro using monoclonal anti-bromodeoxyuridine (anti-BrdU) antibody to dectect BrdU incorporated into cell DNA. However, both NMφs and HMφs showed little proliferation; proliferative indices were less than 2%. This implies that Mφs are barely replicating, and hypercholesterolemia does not stimulate Mφs in this aspect. We conclude that hypercholesterolemia leads to a rapid accumulation of lipids in Mφs, which may be associated with Mφ activation. Such alterations of Mφ functions induced by dietary cholesterol may be potentially important in the development of the fatty streak formation.

Structural changes were studied on the kidney of a potassium-depleted man and on rat kidneys during potassium depletion and repletion. Light and electron microscopy revealed rapid disappearance of intracytoplasmic granules in the renomedullary cells after potassium repletion in our patient as well as in rats. In potassium-depleted rats a series of ultrastructural changes, which were similar to those observed in the human kidney were seen with potassium repletion. Most of the granules were reduced in size and number, with loss of internal structure, shrinkage and condensation of their contents, and were almost totally eliminated by 72 h of potassium repletion. In some endothelial and interstitial cells, the granules were seen to be in the process of being extruded through an area of gap in the plasma membrane. The results indicate that most of the intracytoplasmic granules in the renal medulla rapidly disappeared by intracytoplasmic digestion and the rest of them were probably eliminated by exocytosis during reversal of potassium depletion nephropathy in man and rats.