Amlodipine potentiates metalloproteinase activity and accelerates elastin degradation in a model of aneurysmal disease.
OBJECTIVE
Abdominal aortic aneurysms are characterised by changes in the extracellular matrix of the arterial media, in particular a reduction in elastin concentration. These changes are mediated by increased levels of endogenous matrix metalloproteinases (MMPs). Recently, calcium channel blockers have been shown to increase the proteolytic activity of MMP-2 secreted by vascular smooth muscle cells. It may therefore by hypothesised that calcium antagonists may potentiate the activity of MMPs in aneurysmal disease and thus accelerate AAA expansion. In this study, the ability of amlodipine--a calcium antagonist--to influence elastin degradation, was assessed in a previously described model of aneurysmal disease.


METHODS
Porcine aortic segments (n = 8) were pre-incubated in exogenous pancreatic elastase for 24 h prior to culture in standard conditions for 6 days with 10 and 100 micrograms/l amlodipine. Control segments were cultured both with and without amlodipine and without elastase. At the termination of culture MMPs were extracted from the tissue and quantified by a combination of substrate gel enzymography and immunoblotting. The volume fractions of elastin and collagen were determined by stereological analysis of EVG stained sections.


RESULTS
Gel enzymography demonstrated significantly increased MMP-9 activity in the amlodipine treated segments, median 4.218 vs. 2.809 arbitrary units (p < 0.01) and this elevated activity was reflected in a significant destruction of medial elastin 27.0 vs. 40.5% (p < 0.05).


CONCLUSIONS
Therapeutic ranges of amlodipine significantly enhanced elastin degradation and potentiated MMP-9 activity within the aortic organ cultures.
Boyle
J R
JR
Department of Surgery, Leicester University, U.K.
Loftus
I M
IM
Goodall
S
S
Crowther
M
M
Bell
P R
PR
Thompson
M M
MM
D017311:Amlodipine / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000473:pathology; D001014:Aortic Aneurysm / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D017364:Collagenases / Q000378:metabolism*; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D066298:In Vitro Techniques; D020780:Matrix Metalloproteinase 9; D013552:Swine
D002121:Calcium Channel Blockers; D017311:Amlodipine; D004549:Elastin; D017364:Collagenases; D020780:Matrix Metalloproteinase 9