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
相关论文
共 32 条
[1]   Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb [J].
Arras, M ;
Ito, WD ;
Scholz, D ;
Winkler, B ;
Schaper, J ;
Schaper, W .
JOURNAL OF CLINICAL INVESTIGATION, 1998, 101 (01) :40-50
[2]   EFFECTS OF ACIDIC FIBROBLAST GROWTH-FACTOR ON NORMAL AND ISCHEMIC MYOCARDIUM [J].
BANAI, S ;
JAKLITSCH, MT ;
CASSCELLS, W ;
SHOU, M ;
SHRIVASTAV, S ;
CORREA, R ;
EPSTEIN, SE ;
UNGER, EF .
CIRCULATION RESEARCH, 1991, 69 (01) :76-85
[3]   Lower-extremity edema associated with gene transfer of naked DNA encoding vascular endothelial growth factor [J].
Baumgartner, I ;
Rauh, G ;
Pieczek, A ;
Wuensch, D ;
Magner, M ;
Kearney, M ;
Schainfeld, R ;
Isner, JM .
ANNALS OF INTERNAL MEDICINE, 2000, 132 (11) :880-884
[4]   Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia [J].
Baumgartner, I ;
Pieczek, A ;
Manor, O ;
Blair, R ;
Kearney, M ;
Walsh, K ;
Isner, JM .
CIRCULATION, 1998, 97 (12) :1114-1123
[5]   Mechanisms of angiogenesis and arteriogenesis [J].
Carmeliet, P .
NATURE MEDICINE, 2000, 6 (04) :389-395
[6]  
Davidoff AM, 2001, CLIN CANCER RES, V7, P2870
[7]   HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway [J].
Dimmeler, S ;
Aicher, A ;
Vasa, M ;
Mildner-Rihm, C ;
Adler, K ;
Tiemann, M ;
Rütten, H ;
Fichtlscherer, S ;
Martin, H ;
Zeiher, AM .
JOURNAL OF CLINICAL INVESTIGATION, 2001, 108 (03) :391-397
[8]   Rescue of impaired angiogenesis in spontaneously hypertensive rats by intramuscular human tissue kallikrein gene transfer [J].
Emanueli, C ;
Salis, MB ;
Stacca, T ;
Gaspa, L ;
Chao, J ;
Chao, L ;
Piana, A ;
Madeddu, P .
HYPERTENSION, 2001, 38 (01) :136-141
[9]   Angiogenesis therapy - Amidst the hype, the neglected potential for serious side effects [J].
Epstein, SE ;
Kornowski, R ;
Fuchs, S ;
Dvorak, HF .
CIRCULATION, 2001, 104 (01) :115-119
[10]   Tissue inhibition of angiotensin-converting enzyme activity stimulates angiogenesis in vivo [J].
Fabre, JE ;
Rivard, A ;
Magner, M ;
Silver, M ;
Isner, JM .
CIRCULATION, 1999, 99 (23) :3043-3049