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.
Makaritsis
K P
KP
Departments of Medicine and Biochemistry, Boston University School of Medicine, Boston, Mass 02118, USA.
Gavras
H
H
Du
Y
Y
Chobanian
A V
AV
Brecher
P
P
D000317:Adrenergic alpha-Antagonists / Q000627:therapeutic use*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000172:deficiency*; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001794:Blood Pressure / Q000187:drug effects; D004359:Drug Therapy, Combination; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy; D019808:Losartan / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D011224:Prazosin / Q000627:therapeutic use; D011433:Propranolol / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000187:drug effects; D013997:Time Factors
D000317:Adrenergic alpha-Antagonists; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001057:Apolipoproteins E; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D011433:Propranolol; D019808:Losartan; D019331:NG-Nitroarginine Methyl Ester; D011224:Prazosin