© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Angiotensin-converting enzyme inhibition improves defective angiogenesis in the ischemic limb of spontaneously hypertensive rats
aDepartment of Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan
bNew Product Research Laboratories II, Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan
* Corresponding author. Tel.: +81-3-3964-1211; fax: +81-3-5375-1308 stake{at}blue.ocn.ne.jp
Objectives: Natural angiogenesis has been shown to be impaired in spontaneously hypertensive rats (SHR). The purpose of this study was to determine whether pathological angiogenesis in the setting of tissue ischemia is also impaired in SHR, and to what extent it is modified by angiotensin-converting enzyme (ACE) inhibition. Methods: Ischemia was induced in the hindlimb of SHR by excision of the femoral artery, after which the animals were randomly assigned to receive low-dose perindopril (sub-antihypertensive, 0.2 mg/kg/day), high-dose perindopril (antihypertensive, 2.0 mg/kg/day), or vehicle for 3 weeks. Wistar–Kyoto rats (WKY) with femoral artery excision served as a control group. Results: Tissue ACE activity in SHR was significantly increased compared to WKY (49.4±6.2 vs. 34.0±14.2 IU/mg, P<0.01). Administration of perindopril significantly reduced ACE activity in SHR (low dose: 12.4±2.3; high dose: 11.0±2.1 IU/mg, P<0.005). Angiogenesis of the ischemic limb muscles was significantly impaired at 4 weeks in SHR versus WKY as indicated by the lower capillary density in the former (364.5±43.0 vs. 463.8±63.0/mm2, P<0.05) as well as the reduced hindlimb perfusion assessed by laser Doppler imaging (0.86±0.08 vs. 1.03±0.09, P<0.05). Administration of perindopril significantly augmented both the capillary density (low dose: 494.3±69.8; high dose: 543.9±76.9/mm2, P<0.005) and the limb perfusion (low dose: 1.06±0.15; high dose: 1.05±0.12, P<0.05) of the ischemic limb in SHR. Conclusions: These findings indicate that pathological angiogenesis in the setting of tissue ischemia is impaired in SHR compared with WKY, and that this impairment can be reversed by ACE inhibition. The angiogenic properties of an ACE inhibitor may benefit patients with essential hypertension presenting with lower limb vascular insufficiency.
KEYWORDS ACE inhibitors; Angiogenesis; Capillaries; Collateral circulation; Hypertension; Ischemia
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