Peripheral arterial insufficiency, often apparent as intermittent claudication, is an important cardiovascular disease that lead to significant loss of limb function and work tolerance. Enhanced physical activity represents one useful treatment of affected patients and leads to an enhance muscle performance and exercise tolerance. We have hypothesized that the improved performance evident after increasing physical activity is due to two factors: 1) an improved blood flow made possible by a) development of collateral vessels circumventing a major vessel stenosis, and b) a redistribution of blood flow within the affected limb and whole muscle during activity; and 2) peripheral adaptations that improve aerobic metabolism related to a) an increased mitochondrial content and b) increased capillarity within the affected muscle. A rat model of peripheral arterial insufficiency, created via bilateral stenosis of the femoral artery sufficient to greatly limit active hyperemia but not significantly alter resting blood flow, will be used. Animals will be trained by treadmill running. Improvement in muscle performance will be evaluated during treadmill running in vivo and muscle stimulation in situ. Blood flow to all muscles of the hindlimbs, including individual skeletal muscle fiber sections, will be determined with labeled microspheres during treadmill running to assess the extent of blood flow recovery and flow redistribution within the affected tissue. The significance of the peripheral adaptations will be assessed using an isolated perfused hindlimb preparation where muscle performance and oxygen consumption are measured white blood flow (oxygen delivery) is controlled and modified via perfusion at a site distal to the induced stenosis. Mitochondrial content and muscle capillarity will be determined in specific fiber sections of the distal limb muscles. Additional experiments will evaluate: adaptive changes, induced by exercise training, concurrent with the progressive development of stenosis; retention of the adaptive changes following cessation of training; and, the impact of a mild exercise training program. These unique studies will provide essential information, important to the understanding of intermittent claudication and its clinical management.
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