Patients with obstructive sleep apnea (OSA) are characterized by sustained sympathoexcitation, even awake. This heightened sympathetic activity contributes to hypertension and metabolic abnormalities such as insulin resistance, but the mechanisms by which OSA and its accompanying cyclic intermittent hypoxia (CIH) lead to alterations in sympathetic tone are unknown. Growing evidence, including our own preliminary data, suggests both that OSA patients and rats exposed to CIH each have increased peripheral chemosensitivity and that the peripheral chemoreceptor is essential for the development of sympathoexcitation. These findings suggest that CIH contributes to increased arterial pressure and metabolic changes by inducing a rise in peripheral chemoreflex sensitivity, which in turn enhances resting sympathetic activity. In this project we plan to use a well established animal model of CIH (rats) to better define the response of the carotid chemoreceptors to this pattern of hypoxic exposure, focusing on the augmentation in peripheral chemoreceptor gain and mechanisms that might produce it. Based on our preliminary data we propose to test three hypotheses: 1) that prolonged exposure to CIH induces changes in peripheral chemosensitivity analogous to hypoxic acclimatization; 2) that the changes in hypoxic chemosensitivity after CIH are due to altered activity of specific neuromodulators of peripheral chemoreceptor activity; finally, 3) that the time course of altered expression of each neuromodulator is unique so that chemosensitivity changes with the duration of the exposure. In particular, we speculate that both increased expression of endothelin and decreased expression of nitric oxide synthase in the carotid chemoreceptor contributes to the increased peripheral chemosensitivity observed following exposure to CIH. To test our hypotheses we will assess the peripheral chemoreflex response (ventilation, phrenic nerve activity, renal sympathetic nerve activity) and the response of the carotid bodies (carotid sinus nerve recording) to CIH in a series of experiments using animals exposed to hypoxia 8-hours/day and appropriate sham-exposed control animals. We will use specific pharmacological agonists and antagonists to assess functional changes in endothelin and NOS activity in the carotid body and we will use in situ hybridization to quantify and localize changes in expression of the mRNA for these proteins in the carotid chemoreceptor. Additional studies will assess changes in other carotid body neuromodulators and will assess whether central changes in reflex sympathetic gain further contribute to sympathoexcitation in this model. These studies will enhance our understanding of how sleep apnea contributes to hemodynamic and metabolic abnormalities.