Norepinephrine (NE) is a major catecholamine present in the carotid body, an oxygen sensing organ. Our data demonstrates that NE attenuates the carotid body response to hypoxia. Our hypothesis is: that the carotid body responses to hypoxia are in part tuned by NE by its action on alpha2-adrenergic receptors and that the density and/or binding affinity of these alpha2-receptors decreases with chronic hypoxia and thus contribute to the increase in the carotid body sensitivity to low environmental PO2. This hypothesis will be tested using neurophysiological techniques in combination with pharmacological and biochemical studies of alpha2-adrenergic receptors and NE. Experiments will be carried out in anaesthetized cats and rabbits, the latter for species comparison. Experiments outlined in Specific Aim 1 will examine the contribution of alpha2- receptors to NE induced modulation of carotid body activity. The effects of NE on carotid body activity and chemosensory response to hypoxia will be examined before and after blockade of alpha2- receptors. Parallel experiments will be performed in carotid bodies in vitro to delineate the effects of NE on carotid body blood flow. The role of endogenous NE and alpha2-receptors in hypoxic chemoreception will be assessed on carotid bodies subjected to acute and chronic sympathectomy and by blocking alpha2-receptors. Experiments in Aim 2 will test the hypothesis that hypoxia decreases alpha2-receptor sensitivity and thus will contribute to the enhanced PO2 responses of the carotid body during chronic hypoxia. The alterations in alpha2-receptor sensitivity will be tested by determining the carotid body responses to NE and alpha2-agonists. Radioligand binding assay and autoradiographic studies proposed in Aim 3 will characterize the alpha2-adrenergic binding sites in the carotid body and will determine whether hypoxia and denervation of the carotid bodies will affect the agonist binding at the receptors. The career development goals are to continue extensive involvement in current research award and to extend my education into new fields, including molecular biological approaches and cellular biology, including intracellular second messenger systems and biophysical techniques. These techniques are relevant to my future research in arterial chemoreception. The RCDA Award will replace and provide additional salary support for the proposed studies, as well as provide support for time to learn and apply new techniques. Thus, this award will facilitate and promote my career toward the long-term goal of establishing my academic career in respiratory physiology.
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