Amlodipine reduces AngII-induced aortic aneurysms and atherosclerosis in hypercholesterolemic mice.
BACKGROUND
The purpose of this study was to determine effects of amlodipine, a dihydropyridine calcium channel blocker, on development of angiotensin II (AngII)-induced vascular pathologies.


RESULTS
Male LDL receptor -/- mice were infused with vehicle, amlodipine (5 mg/kg/d), AngII (1,000 ng/kg/min), or AngII + amlodipine for 4 weeks through osmotic pumps (n=10/group). Mice were fed a saturated fat-enriched diet for 1 week prior to pump implantation and during 4 weeks of infusion. Infusion of amlodipine resulted in plasma concentrations of 32 ± 2 ng/ml and 27 ± 2 ng/ml for mice in saline + amlodipine and AngII + amlodipine groups, respectively. This infusion rate of amlodipine did not affect AngII-induced increases in systolic blood pressure. Three of 10 (30%) mice infused with AngII died of aortic rupture, while aortic rupture did not occur in mice co-infused with AngII + amlodipine. Suprarenal aortic width and intimal area of ascending aortas were measured to define aortic aneurysms. In the absence of AngII infusion, amlodipine did not change suprarenal aortic width and ascending aortic area. Infusion of AngII led to profound increases of suprarenal aortic width (saline + vehicle versus AngII + vehicle: 0.86 ± 0.02 versus 1.72 ± 0.26 mm; P=0.0006), whereas co-infusion of AngII and amlodipine diminished abdominal dilation (1.02 ± 0.14 mm; P=0.003). As expected, AngII infusion increased mean intimal area of ascending aortas (saline + vehicle versus AngII + vehicle: 8.5 ± 0.3 versus 12.5 ± 1.1 mm(2); P=0.001), while co-infusion of AngII and amlodipine ablated dilation of the ascending aorta (8.6 ± 0.2 mm(2); P=0.03). Co-administration of amlodipine also significantly attenuated AngII-induced atherosclerosis in the thoracic region as quantified by percent lesion area (AngII + vehicle versus AngII + amlodipine: 5.8 ± 2.1 % versus 0.3 ± 0.1%; P=0.05).


CONCLUSIONS
Amlodipine inhibited AngII-induced aortic aneurysms in both the abdominal and ascending regions, and atherosclerosis in hypercholesterolemic mice.
Saha Cardiovascular Research Center, University of Kentucky, Lexington, Kentucky, United States of America.
Xiaofeng
X
Chen
Debra L
DL
Rateri
Deborah A
DA
Howatt
Anju
A
Balakrishnan
Jessica J
JJ
Moorleghen
Andrew J
AJ
Morris
Richard
R
Charnigo
Lisa A
LA
Cassis
Alan
A
Daugherty
D017311:Amlodipine / Q000627:therapeutic use*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001014:Aortic Aneurysm / Q000139:chemically induced* / Q000188:drug therapy*; D050197:Atherosclerosis / Q000139:chemically induced* / Q000188:drug therapy*; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism
D011973:Receptors, LDL; D000804:Angiotensin II; D017311:Amlodipine