Patients with heart failure (HF) typically demonstrate a reduced work capacity when compared to normal individuals. This reduced work capacity has been attributed, in park to the early onset muscular fatigue and has been correlated with reductions in blood flow to working skeletal muscle. The primary objective of this proposal is to identify the factors contributing to the reductions in skeletal muscle blood flow in the HF state. Towards this objective, a surgically induced myocardial infarction (MI) or a sham operation (SHAM) will be performed on adult female Wistar rats. Following 6 weeks of recovery, the extent of LV dysfunction and HF produced will be determined by measuring LV and RV pressures in vivo in the awake resting animal. The vascular transport capacity (VTC) of the hind limb musculature will then be assessed using the isolated hindquarters perfusion technique. The different components of the VTC, the vascular flow capacity and capillary exchange capacity, will be determined in NU rats and analyzed as a function of LV infarct size (small, medium, large and extensive infarcts) and compared to both components in SHAM rats. In addition, the flow component of the VTC of the hind limb musculature will be examined in individual muscles with radiolabeled microspheres. This experimental approach will allow us to determine if the decrement in the VTC of the hind limb musculature of MI rats becomes greater as the size of the infarct becomes larger, the amount of LV dysfunction worsens and as the degree of HF progresses from the compensated to the decompensated congestive state. We will also determine whether the formation of interstitial edema is one of the mechanisms responsible for limiting flow in the skeletal muscle of MI rats by reducing the amount of fluid retained in the extravascular space of rats with diuretic therapy and by examining the effects of this intervention on the VTC of the hind limb musculature. Finally, we will determine whether endurance exercise training can ameliorate the decrements in the VTC of the hind limb musculature of MI rats. Altogether, these studies will corroborate our preliminary studies where decrements in the vascular flow capacity of hind limb musculature of rats with a large MI were found. They will provide a better understanding of the mechanisms involved that produce the decrements in skeletal muscle blood flow in the BF state and they will prove useful in the development of clinical strategies for mating this debilitating disease.
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