Very-low-dose combination of the angiotensin-converting enzyme inhibitor perindopril and the diuretic indapamide induces an early and sustained increase in neovascularization in rat ischemic legs

被引:30
|
作者
Silvestre, JS [1 ]
Kamsu-Kom, N [1 ]
Clergue, M [1 ]
Duriez, M [1 ]
Lévy, B [1 ]
机构
[1] Univ Paris, Hop Lariboisiere, INSERM, U541, F-75475 Paris 10, France
关键词
D O I
10.1124/jpet.102.040014
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
After acute ischemia of tissues, neovascularization must be sufficient and fast enough to preserve tissue integrity and organ function, and may thus be considered as a therapeutic strategy. This study examined the possible role of the very-low-close combination of perindopril (angiotensin-converting enzyme inhibitor) and indapamide (diuretic), used first-line in the treatment of essential hypertension, on ischemia-induced angiogenesis. Ischemia was produced by artery femoral occlusion in rats treated or not with the very-low-close combination (perindopril 0.76 mg/kg/day + indapamide 0.24 mg/kg/day) or each component given alone at the same dosage for 3 and 28 days. At day 3, angiographic vessel density and laser Doppler perfusion data showed significant improvement in ischemic/nonischemic leg ratio by, respectively, 1.9-fold and 1.5-fold in rats treated with the very-low-close combination when compared with controls (p < 0.05). This was associated with an increase in vascular endothelial growth factor (VEGF; 2.2-fold) and endothelial nitric-oxide synthase (1.6-fold) protein content in the ischemic hindlimb, assessed by Western blot. At day 28, the very-low-close combination (3- and 1.6-fold) and perindopril alone (1.8- and 1.4-fold) and indapamide alone (2.0- and 1.4-fold) increased the angiograhic score and blood flow perfusion, respectively, in reference to controls (p < 0.05). Furthermore, addition of VEGF-neutralizing antibody (2.5 mug/kg twice a week) or NOS inhibitor (N-G-nitro-L-arginine methyl ester, 10 mg/kg/day) prevented the pro-angiogenic effect induced by the perindopril/indapamide combination. The very-low-close combination of perindopril and indapamide induces an early and sustained effect on the revascularization process observed in ischemic tissue and may provide a favorable therapeutic neovascularization after ischemia.
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收藏
页码:1038 / 1043
页数:6
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