When blood flow in a large artery is increased, the vessel dilates. This flow dependent dilation is not mediated by myogenic mechanisms, an ascending message from the microcirculation, Alpha or Beta receptors, or prostaglandins. We have recently demonstrated that the dilation is endothelial cell dependent, involves both a non-prostaglandin metabolite of arachidonic acid and cyclic GMP, and is very sensitive to decreases in ionized plasma calcium. This proposal is designed to examine the physiological significance of flow dependent dilation and the pathophysiologic importance of its absence. Specifically, experiments are designed to determine the effect of shear stress on the dilation response and to define the precise role for calcium in endothelial dependent relaxation in vivo. We will determine the contribution of flow dilation in exercise hyperemia during 3 Hz. exercise and in chronically prepared dogs trained to run on a treadmill. We will evaluate the effects of hypercholesterolemia, atherosclerosis, and diabetes on endothelial dependent dilations in vivo and correlate these with in vitro vasoactivity. We will assess the role of intra-endothelial cell communication in the """"""""ascending dilation"""""""" seen with the distal injection of acetylcholine. Finally, we will investigate the effect of canine heartworm (D. immitis) infection on femoral artery vasoreactivity in vivo and in vitro. Our preliminary data shows that adult heartworms, in the pulmonary circulation, adversely influences femoral artery reactivity.
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