In the present proposal we plan to continue pursuing the hypothesis that the diabetic state--greater than microvascular changes--greater than endoneurial hypoxia --greater than further microvascular changes and that this vicious cycle is partly responsible for the pathogenesis of chronic progressive diabetic neuropathy. Our studies will be in 4 directions. First, we will further study if endoneurial hypoxia is present in chronic diabetic neuropathy by measuring nerve blood flow (NBF) and endoneurial oxygenation in chronic (8 months) spontaneous autoimmune diabetes (SAD) in the BB-Wistar rat; we will also measure endoneurial oxygen tensions in the sural nerves of patients with diabetic neuropathy. Second, we plan to test the hypothesis that neurovascular reactivity is altered in chronic SAD neuropathy in the BB Wistar rat. We will evaluate the hierachy of NBF regulation (terminal artery, epineurial arteriole, capillary), information that is currently unavailable. The role of the epineurial arteriole and the terminal artery in the regulation of NBF will be monitored using computerized videoangiology (CVA). The differential roles of epineurial and endoneurial capillaries will be studied using simultaneous measurements of epineurial and endoneurial NBF using pairs of platinum micro-electrodes and hydrogen polarography. To study the effects of physiologic perturbations on dynamics alterations of composite NBF we will use a laser doppler flowmeter. We recently found that mammalian nerves that are rendered severely ischemic for longer than 15 minutes remain in spasm. We plan to examine why the capillary remains closed. We also plan to study mechanisms of increasing nerve blood flow in normal and pathologic nerves. A number of vasoactive agents including PGE1, pentoxifylline and ketanserine are used in the treatment of diabetic microangiopathy, including nerve microangiopathy, but the mechanism of action of these agents on nerve microvasculature is currently not known. These physiologic studies will be augmented by measurements of high energy phosphates, catecholamines and prostaglandins. Third, studies are underway to determine if chronic established STZ diabetic neuropathy is in part reversible with hyperbaric oxygenation. The studies will be extended to chronic SAD neuropathy in the BB Wistar rat. Fourth, we plan to perform a mathematical simulation of oxygen release, radial and axial diffusion and their interactions in mammalian peripheral nerve. We will relate experimental to stimulated data, evaluate hypotheses and apply this methodology to human nerve. These studies will supplement and possibly reduce the need for the number of animal experiments.