CIRCULATORY AND METABOLIC ADAPTATIONS IN ISCHEMIC LIMBS

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This project will probe for and document the adaptive response of limb muscle to a limited blood supply. The overall goal of this project is to test for the existence and document the characteristics of the dynamic and adaptive interrelationships among (1) total limb blood flow and blood flow to a specific skeletal muscle (gastrocnemiusplantaris), (2) the capacity of calf muscle to perform work, and (3) the metabolic co of this work during graded intensities of steady-state exercise of the normal rat. We will focus on the ischemic lower limb of the rat as an animal model and study it at intervals after ligation of the superficial femoral artery and in response to graded exercise training. We will assess the high-energy phosphate metabolic state, intracellular pH, and muscle mechanical performance during the phases of acute and chronic ischemia, both at rest and in response to stimulation. The mechanical work will be assessed by measuring the muscle force during nerve stimulation. The metabolic cost of this contractile activity will be assessed from the changes in muscle content of high-energy phosphate compounds measured by nuclear magnetic resonance 31P spectroscopy. Content of key metabolic enzymes and isoforms of myosin and other proteins will be measured. We will document by angiography the time course and extent of collateral circulation development, and assess its functional capacity by direct blood flow measurements. We will test the hypotheses that the normal and ischemic limb is both hemodynamically and biochemically adaptable, and that the adaptive responses to femoral artery ligation and stenosis are similar to those occurring in normal exercise training. Our working hypothesis is that, with a reduction in flow that disturbs the balance between energy supply and demand, there is an adaptation not only of the vasculature but also the mechanical, myosin and other protein isoenzymes and metabolic characteristics of the limb musculature. The postulated adaptations are expected to be those that decrease the metabolic cost per unit work, i.e., adaptation towards a more aerobic and slow-twitch muscle. Our long range objective is to work out these same parameters with respect to patients with peripheral vascular disease.