The carotid body, an arterial chemoreceptor organ sensitive to O2 and CO2, possesses specialized pre-neural type I cells which contain an array of neurotransmitter agents. Current views hold that exposure to chemoreceptor stimuli initiates a complex cascade of transductive events in these cells, culminating in the release of excitatory transmitter agent(s) which activate closely apposed sensory fibers of the carotid sinus nerve (CSN). Numerous biophysical and neurochemical investigations have partially elucidated the mechanisms underlying chemotransduction and chemotransmission in this organ. However, it has become increasingly apparent that the chemosensitivity of the type I cell/sensory nerve ending complex is modulated by powerful extrinsic mechanisms involving direct neural innervation of this receptor complex, and by important intrinsic cellular mechanisms which are triggered by chemostimulation of the organ. Direct neural control consists of 1), an unidentified neural inhibitory component traveling in the CSN, and 2), sympathetic fibers in the gangliomerular nerve (GGN) which contact type I cells but whose function is likewise uncharacterized. Equally ill-defined are the intrinsic cellular mechanisms by which chemostimulation can invoke dramatic changes in the receptor complex, including type I cell hypertrophy, hyperplasia, and altered neurotransmitter levels and chemoreceptor thresholds. The experiments formulated here will use a multidisciplinary approach to investigate these neural and cellular mechanisms of chemoreceptor modulation. Our research plan consists of three specific aims: 1) we will identify the neurons and the neurotransmitter mechanisms involved in chemoreceptor inhibition via the CSN. These experiments utilize immunocytochemical, neurochemical and electrophysiological techniques to elucidate the roles of two putative inhibitory agents, nitric oxide and atrial natriuretic peptide, in modulation of chemoreceptor activity. 2) Studies of chemoreceptor modulation by the sympathetic innervation will use a unique in vitro superfusion chamber to assess direct preganglionic vs. postganglionic effects on type I cells and CSN activity. 3) Finally, the effects of chemostimulation and chronic denervation on cellular/molecular processes in type I cells will be evaluated in experiments designed to study the role of gene expression in regulation of the chemoresponse. These experiments involve the use of modern gene amplification and hybridization techniques. The ultimate aim of these studies is to clarify the synaptic and cellular processes which are key to chemoreceptor adaptations associated with natural stimulation.