This proposal seeks to define the mechanics of cochlear blood flow control. The proposal offers the hypothesis that nitric oxide (NO), a molecule with both vasoactive and neuroactive capacity, is one factor contributing to vascular tone in the cochlea. The sympathetic neural input is another factor, along with myogenic mechanisms. The study is in three parts. 1) Examines the systems that control cochlear blood flow in the normal cochlea. Responsiveness of smooth muscle is measured following manipulations of the sympathetic neural innervation and oxygen respiration. Measures of myogenic activity are accomplished by measuring the speed and amount of the blood flow change (by laser Doppler flowmetry) following compressions of the feeding arteries to the cochlea. 2) Measures the amount of sound-induced sensitivity loss in chronic experiments as a function of oxygen delivery to the cochlea. Oxygen concentration in the organ of Corti is measured using oxygen sensing microelectrodes. This is done in order to verify and study the exact oxygen deficit and the consequential energy shortfall in the cochlea. A """"""""functional deficit model"""""""" is also explored, where a small topographic vascular lesion in the cochlea is created by light activation of the photothrombic agent, rose bengal. In both of these experiments, the relationship of the vascular change to the activity of the organ of Corti will be measured using the otoacoustic and cochlear microphonic distortion products. Direct observations of the vessels in the stria vascularis also will be made during sound stimulation. The velocity of the flowing blood in capillaries and the diameters of the capillaries will be determined. 3) determines the role of NO in cochlear blood flow control. First, the endogenous level of NO causing vasodilation of cochlear blood vessels will be determined by applying competitive blockers of NO synthase. The blockers will be given into the cochlea by perfusion and by systemic administration. The direct effect of NO on cochlear blood vessels will be measured by intravital microscopy. The study will also determine the toxicity of NO on sensory function. Taken as a whole, the aims of this proposal will establish the roles of intracochlear oxygenation, NO, and the sympathetic nervous system to the cochlea in establishing the basal cochlea blood flow and vascular reactivity.
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