title: 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.
abstract: 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U541, Hôpital Lariboisière, Université Paris, Paris, France.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Silvestre
authors.forename: Nyam
authors.initials: N
authors.lastname: Kamsu-Kom
authors.forename: Michel
authors.initials: M
authors.lastname: Clergue
authors.forename: Micheline
authors.initials: M
authors.lastname: Duriez
authors.forename: Bernard I
authors.initials: BI
authors.lastname: Lévy
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D000818:Animals; D004232:Diuretics / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D016228:Endothelial Growth Factors / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D007190:Indapamide / Q000008:administration & dosage*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D020913:Perindopril / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D004232:Diuretics; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D007190:Indapamide; D020913:Perindopril