H. T. Yang

Angiotensin‐Converting Enzyme Inhibition Increases Exercise Tolerance and Muscle Blood Flow in Rats with Peripheral Arterial Insufficiency

To determine the effect of angiotensin‐converting enzyme (ACE) inhibition on exercise tolerance and muscle blood flow (BF) to ischemic limbs, both femoral arteries of male Sprague‐Dawley rats (≅325 g) were surgically stenosed. Rats were either active (treadmill run, 20 m/min @ 15% grade, 5 d/wk for 3 wk) or sedentary (limited to cage activity), and assigned to one of three doses of zabicipril at 0.0 (zero), 0.3 (low), and 3.0 (high) mg · kg−1 · d−1 administered via food intake (N=14–15/group). After 3 weeks, the left carotid and caudal arteries were catheterized under anesthesia for BF measurement later in the day. Muscle BF was determined during exercise at two treadmill speeds (20 and 30 m/min) with 85Sr and 141Ce labeled microspheres to ensure a peak BF. Plasma ACE was inhibited 31%, 65% in the low‐ and high‐dose sedentary rats and 75%, 74% in the low‐ and high‐dose active animals, respectively (P < 0.001). Angiotensin‐converting enzyme inhibition improved exercise tolerance by 3 weeks, at a low speed (20 m/min) in the sedentary groups (P < 0.025) and in a dose‐dependent manner at a higher speed (25 m/min) in the active groups (P < 0.001). Blood pressures and heart rates during running were not different among groups. However, total hindlimb BF, reduced to approximately 33% of normal by femoral stenosis, was increased by ACE inhibition and chronic activity in a dose‐dependent manner (P < 0.025). Blood flows to the plantar flexors were most improved (≅20–40%; to 124 mL · min−1 · 100 g−1) in the high‐dose groups (P < 0.01). The higher run speed did not increase BF above the low speed. Training adaptation, indicated by an enhanced muscle mitochondrial content (P < 0.001), was similar for low‐ and high‐dose active animals. Our results indicate that ACE inhibition improves BF to ischemic muscles and, together with chronic physical activity, improves exercise tolerance. The results from this study support those advocating ACE inhibition in managing appropriate patients with peripheral arterial insufficiency.

The Influence of Pentoxifylline and Torbafylline on Muscle Blood Flow in Animals With Peripheral Arterial Insufficiency

The potential of pentoxifylline to enhance blood flow to relatively ischemic muscle during running was evaluated in rats with peripheral arterial insufficiency. Femoral artery stenosis, sufficient to limit exercise hyperemia but not affect resting blood flow, was surgically induced in adult male rats (∼350 g). Day three after stenosis, rats were assigned to either a control (N = 14) or treatment (N = 14) group and exercised 5 days a week for 3 weeks. Exercise tolerance of rats fed pentoxifylline (34 ± 1.3 mg/kg/day) or an analog (torbafylline; 34 ± 2.3 mg/kg/day) increased more (P < .001) than control rats in the third week of treatment. This was evidenced by a higher treadmill speed and longer duration of running. Blood flows determined with 85Sr and 141Ce labeled 15μ spheres at low (20 m/min) and high (30–35 m/min) treadmill speeds were similar for each group and ∼50% of that found in normal nonstenosed rats. Blood flows to the entire hindlimb, to the proximal and distal hindlimb segments, and to individual muscle fiber sections were not different between control and pentoxifylline groups. Thus, the increase in exercise tolerance could not be attributed to an increase in muscle blood flow. Rather, an enhanced oxygen extraction by the working limb muscles should lead to the increased VO2, required by the faster running speed in the pentoxifylline rats. This suggests that pentoxifylline may act to improve microvascular flow heterogeneity in working muscle. Our findings support clinical evidence that pentoxifylline is effective in managing patients with peripheral arterial insufficiency.