dihydropyridines and Aortic-Aneurysm--Abdominal

Although systemic hypertension is closely associated with aortic aneurysm (AA) formation, there are many patients with AA without hypertension. In these patients, an inflammation-mediated progression of aneurysmal disease is likely responsible for AA growth and eventual rupture. Unfortunately, there remains no reproducible and durable small animal model of aortic aneurysmal disease, the development of which would enable the investigation of the pathophysiology of this vexing condition. The first aim was to establish a useful wild-type mouse model of AA with low mortality. The second aim was to use this model to assess the protective effect of azelnidipine, a new calcium channel blocker, against the progression of the AA independent of its antihypertensive effect.. Angiotensin II and β-aminopropionitrile (a lysyl oxidase inhibitor) were administrated subcutaneously in 7-week-old C57BL/6J mice using an osmotic minipump for 4 weeks to generate a wild-type mouse model of AA. Concurrently, azelnidipine (a calcium channel blocker) or a placebo was administrated orally for 4 weeks. Mice were humanely killed and assessed at the end of the 4 weeks of pharmacologic manipulation.. The combined infusion of angiotensin II and β-aminopropionitrile induced degenerative aneurysm of the thoracic and/or abdominal aorta (11/12; 92%). The majority of aneurysms were located in the distal aortic arch and suprarenal abdominal aorta. Although there was no difference in systolic blood pressure between the control and azelnidipine-treated groups, azelnidipine significantly reduced the incidence of AA (2/11; 18%). Azelnidipine treatment reduced the pathologic findings normally associated with aneurysm formation within the aortic wall. Azelnidipine also reduced the number of macrophage antigen-3 (MAC-3)-positive cells in the periaortic adipose tissue and reduced the gene expression levels of tumor necrosis factor-alpha and matrix metalloproteinase-2 and -9 within the aortic wall.. This study demonstrates that combined treatment with angiotensin II and β-aminopropionitrile induces degenerative AAs in wild-type mice, and azelnidipine prevents aneurysm progression via its anti-inflammatory effect.

Topics: Aminopropionitrile; Angiotensin II; Animals; Anti-Inflammatory Agents; Aorta, Abdominal; Aorta, Thoracic; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Disease Progression; Inflammation Mediators; Macrophages; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Sirtuin 1; Time Factors; Tumor Necrosis Factor-alpha

We investigated the changes of matrix metalloproteinase (MMP) -9 in the peripheral blood samples of patients undergoing endovascular aneurysm repair (EVAR) for abdominal aortic aneurysms (AAAs), and the effect of azelnidipine on plasma MMP-9 levels in those patients. Levels of MMP-9 were measured in 22 patients who underwent EVAR for AAAs, and results were compared between a group receiving 16 mg azelnidipine daily (n=12) and a control group without azelnidipine (n=10). Measurements were taken preoperatively, and at 1 month and 3 months, postoperatively. Patients without endoleaks after EVAR showed a significant decrease in mean plasma MMP-9 levels (preoperative value: 39.5+/-14.3 ng/mL, after 1 month: 25.0+/-12.6, after 3 months: 28.2+/-10.2 ng/mL; P=0.004). In contrast, no significant decreases in mean plasma MMP-9 levels were observed in the patients with endoleaks after EVAR (preoperative value: 37.5+/-9.0 ng/mL, after 1 month: 26.8+/-8.4, after 3 months: 38.5+/-15.7 ng/mL; P=0.219). Moreover, among patients without endoleaks, those receiving azelnidipine showed a significantly greater decrease in the mean plasma MMP-9 levels for 3 months postoperatively (preoperative value: 47.7+/-13.2 ng/mL, after 1 month: 26.6+/-12.8, after 3 months: 26.1+/-11.4 ng/mL; P0.001) compared with the control group without endoleaks (preoperative value: 31.3+/-10.5 ng/mL, after 1 month: 33.4+/-12.1, after 3 months: 30.3+/-9.1 ng/mL; P=0.792). These results showed that azelnidipine treatment in patients without endoleak after EVAR was associated with a significant decrease in mean plasma MMP-9 levels for 3 months postoperatively.

Topics: Aged; Aortic Aneurysm, Abdominal; Azetidinecarboxylic Acid; Blood Vessel Prosthesis Implantation; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Male; Matrix Metalloproteinase 9; Middle Aged

Azelnidipine has recently been recognized in vascular remodeling. However, the effects of azelnidipine on aneurysmal disease have not yet been studied. The aim of this study was to evaluate whether azelnidipine can inhibit a further expansion of aneurysmal disease.. Experimental abdominal aortic aneurysms (AAAs) were created in a rat model by perfusing elastase. The rats in the first group received no treatment (n=10). In the second group (n=10) azelnidipine (2 mg/kg) was administered to the animals from 3 days before perfusion. The aortic diameter (AD) was measured at the time of initial surgery and death on postoperative day 14. The production of matrix metalloproteinases (MMP)-2 and -9 was analyzed by gelatin zymography.. The aortic diameter was smaller in the azelnidipine group than in the control (7.875+/-1.454 vs 10.745+/-0.551 mm, P<0.01). the active MMP-2 and MMP-9 levels decreased in the azelnidipine group. Hematoxylin-eosin and elastin staining revealed fewer changes in the inflammatory infiltrate and degradation of elastin in the azelnidipine group.. Azelnidipine reduced the expansion of experimental AAAs. Azelnidipine therefore appears to influence the inflammatory oxidative response seen in AAAs while also decreasing the MMP-2 and MMP-9 levels. In addition, azelnidipine inhibited aortic dilatation.

Topics: Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Azetidinecarboxylic Acid; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Disease Progression; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Rats; Rats, Wistar