Matthew A Ziegler1, Matthew R DiStasi2, Steven J Miller3, Michael C Dalsing1, Joseph L Unthank4. 1. Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana. 2. Departments of Pediatrics, and Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana. 3. Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana; Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana. 4. Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana; Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address: junthank@iupui.edu.
Abstract
BACKGROUND: Lack of techniques to assess maximal blood flow capacity thwarts the use of rodent models of arterial insufficiency to evaluate therapies for intermittent claudication. We evaluated femoral vein outflow (VO) in combination with stimulated muscle contraction as a potential method to assess functional hind limb arterial reserve and therapeutic efficacy in a rodent model of subcritical limb ischemia. MATERIALS AND METHODS: VO was measured with perivascular flow probes at rest and during stimulated calf muscle contraction in young, healthy rats (Wistar Kyoto, WKY; lean Zucker rats, LZR) and rats with cardiovascular risk factors (spontaneously hypertensive [SHR]; obese Zucker rats [OZR]) with acute and/or chronic femoral arterial occlusion. Therapeutic efficacy was assessed by administration of Ramipril or Losartan to SHR after femoral artery excision. RESULTS: VO measurement in WKY demonstrated the utility of this method to assess hind limb perfusion at rest and during calf muscle contraction. Although application to diseased models (OZR and SHR) demonstrated normal resting perfusion compared with contralateral limbs, a significant reduction in reserve capacity was uncovered with muscle stimulation. Administration of Ramipril and Losartan demonstrated significant improvement in functional arterial reserve. CONCLUSIONS: The results demonstrate that this novel method to assess distal limb perfusion in small rodents with subcritical limb ischemia is sufficient to unmask perfusion deficits not apparent at rest, detect impaired compensation in diseased animal models with risk factors, and assess therapeutic efficacy. The approach provides a significant advance in methods to investigate potential mechanisms and novel therapies for subcritical limb ischemia in preclinical rodent models.
BACKGROUND: Lack of techniques to assess maximal blood flow capacity thwarts the use of rodent models of arterial insufficiency to evaluate therapies for intermittent claudication. We evaluated femoral vein outflow (VO) in combination with stimulated muscle contraction as a potential method to assess functional hind limb arterial reserve and therapeutic efficacy in a rodent model of subcritical limb ischemia. MATERIALS AND METHODS: VO was measured with perivascular flow probes at rest and during stimulated calf muscle contraction in young, healthy rats (Wistar Kyoto, WKY; lean Zucker rats, LZR) and rats with cardiovascular risk factors (spontaneously hypertensive [SHR]; obese Zucker rats [OZR]) with acute and/or chronic femoral arterial occlusion. Therapeutic efficacy was assessed by administration of Ramipril or Losartan to SHR after femoral artery excision. RESULTS: VO measurement in WKY demonstrated the utility of this method to assess hind limb perfusion at rest and during calf muscle contraction. Although application to diseased models (OZR and SHR) demonstrated normal resting perfusion compared with contralateral limbs, a significant reduction in reserve capacity was uncovered with muscle stimulation. Administration of Ramipril and Losartan demonstrated significant improvement in functional arterial reserve. CONCLUSIONS: The results demonstrate that this novel method to assess distal limb perfusion in small rodents with subcritical limb ischemia is sufficient to unmask perfusion deficits not apparent at rest, detect impaired compensation in diseased animal models with risk factors, and assess therapeutic efficacy. The approach provides a significant advance in methods to investigate potential mechanisms and novel therapies for subcritical limb ischemia in preclinical rodent models.
Authors: A T Hirsch; M H Criqui; D Treat-Jacobson; J G Regensteiner; M A Creager; J W Olin; S H Krook; D B Hunninghake; A J Comerota; M E Walsh; M M McDermott; W R Hiatt Journal: JAMA Date: 2001-09-19 Impact factor: 56.272