Differential effects of AT1 receptor and Ca2+ channel blockade on atherosclerosis, inflammatory gene expression, and production of reactive oxygen species.
Angiotensin II receptor blockade has been shown to inhibit atherosclerosis in several different animal models. We sought to determine if this effect was the result of blood pressure reduction per se or a result of the anti-inflammatory effects of receptor blockade. ApoE-deficient mice were fed a high fat diet and treated with either an angiotensin II receptor antagonist, candesartan (0.5 mg/kg/day, s.c.) or a calcium channel blocker, amlodipine (7.5 mg/kg/day, mixed with food). Atherosclerotic lesion area, aortic inflammatory gene expression as well as aortic H2O2 and superoxide production were assayed. We found that candesartan but not amlodipine treatment dramatically attenuated the development of atherosclerosis despite a similar reduction in blood pressure. Similarly, candesartan treatment inhibited aortic expression of inflammatory genes and production of reactive oxygen species, effects not seen with amlodipine. These data demonstrate that angiotensin II receptor blockade inhibits atherosclerosis by reducing vascular oxidative stress and inflammatory gene production independent of blood pressure reduction.
Doran
Derek E
DE
Division of Cardiology, Department of Medicine, Emory University School of Medicine and the Atlanta VA Medical Center, Atlanta, GA, United States.
Weiss
Daiana
D
Zhang
Yong
Y
Griendling
Kathy K
KK
Taylor
W Robert
WR
D017311:Amlodipine / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism*; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D015220:Calcium Channels / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007249:Inflammation; D051379:Mice; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D015220:Calcium Channels; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D017311:Amlodipine; D006861:Hydrogen Peroxide; C081643:candesartan