Alpha1-adrenergic plus angiotensin receptor blockade reduces atherosclerosis in apolipoprotein E-deficient mice

-We have used the apolipoprotein E (apoE)-deficient mouse model to determine whether both the angiotensin II type 1 (AT1) and the alpha1-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 1.5x10(5) microm2 (P<0.001) and significantly reduced blood pressure to 85+/-5 mm Hg. Treatment with NG-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 AT1 and alpha1-adrenergic receptor activation.