α 1 -Adrenergic Plus Angiotensin Receptor Blockade Reduces Atherosclerosis in Apolipoprotein E–Deficient Mice

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Abstract
—We have used the apolipoprotein E (apoE)–deficient mouse model to determine whether both the angiotensin II type 1 (AT 1 ) and the α 1 -adrenergic receptors influence arteriosclerotic changes in this hyperlipidemic animal model. Mice were treated with antihypertensive drugs beginning at 9 weeks of age, and aortic atherosclerosis was measured after 12 weeks of treatment. Systolic blood pressure in the untreated apoE-deficient mouse averaged 104 mm Hg throughout the treatment period. Prazosin at a dose of 7.5 mg · kg −1 · d −1 was ineffective in attenuating atherosclerosis and did not significantly reduce blood pressure. Losartan, at dosages of either 20 or 30 mg · kg −1 · d −1 , also did not influence atherosclerosis and had only a slight blood pressure–lowering effect. However, combined treatment with both prazosin and losartan markedly reduced atherosclerotic lesion development from an average lesion size per section of 2.6 to 1.5×10 5 μm 2 ( P N G -nitro- l -arginine methyl ester (40 mg · kg −1 · d −1 ) produced significant elevations of blood pressure (127±3.8 mm Hg) but had no effect on the development of atherosclerosis. None of the treatments used affected plasma cholesterol throughout the 12-week period. These studies suggest that the vascular changes associated with atherosclerosis are influenced by a combination of AT 1 and α 1 -adrenergic receptor activation.