Silvestre Jean-Sébastien, Kamsu-Kom Nyam, Clergue Michel, Duriez Micheline, Lévy Bernard I
Institut National de la Santé et de la Recherche Médicale U541, Hôpital Lariboisière, Université Paris, Paris, France.
J Pharmacol Exp Ther. 2002 Dec;303(3):1038-43. doi: 10.1124/jpet.102.040014.
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-dose 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-dose 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-dose 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-dose 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 microg/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-dose 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.
组织急性缺血后，新生血管形成必须足够充分且迅速，以维持组织完整性和器官功能，因此可被视为一种治疗策略。本研究考察了一线用于治疗原发性高血压的培哚普利（一种血管紧张素转换酶抑制剂）与吲达帕胺（一种利尿剂）的极低剂量组合对缺血诱导的血管生成的可能作用。通过股动脉闭塞在大鼠中制造缺血模型，将大鼠分为接受极低剂量组合（培哚普利0.76毫克/千克/天 + 吲达帕胺0.24毫克/千克/天）或相同剂量的各组分单独给药处理组，以及未处理的对照组，给药3天和28天。在第3天，血管造影血管密度和激光多普勒灌注数据显示，与对照组相比，接受极低剂量组合治疗的大鼠缺血/非缺血腿比率分别显著提高了1.9倍和1.5倍（p < 0.05）。通过蛋白质印迹法评估发现，这与缺血后肢中血管内皮生长因子（VEGF；2.2倍）和内皮型一氧化氮合酶（1.6倍）蛋白含量增加有关。在第28天，与对照组相比，极低剂量组合（分别为3倍和1.6倍）、单独使用培哚普利（分别为1.8倍和1.4倍）以及单独使用吲达帕胺（分别为2.0倍和1.4倍）分别提高了血管造影评分和血流灌注（p < 0.05）。此外，添加VEGF中和抗体（2.5微克/千克，每周两次）或NOS抑制剂（N(G)-硝基-L-精氨酸甲酯，10毫克/千克/天）可阻止培哚普利/吲达帕胺组合诱导的促血管生成作用。培哚普利和吲达帕胺的极低剂量组合对缺血组织中的血管再通过程具有早期和持续的作用，可能为缺血后提供有利的治疗性新生血管形成。
