The objective of this project is to quantify the cellular adaptations in carotid body function occurring with in vivo acclimatization to chronic hypoxia (stimulating high altitude) and with combined chronic hypoxia and hypercapnia (simulating chronic lung disease). The carotid body is the primary source of the hypoxic ventilatory drive, but very little is known about the electrophysiological adaptations of the carotid body to chronic hypoxia. Patch clamp techniques will be used to record currents associated with potassium, sodium and calcium ion channels in glomus cells isolated from control and acclimatized rats. We will test for changes in glomus cell ion channel activity and membrane potential associated with acclimatization to O2 and Co2 stimuli. To determine the specificity of measured adaptations to the carotid bogy, we will compare acclimatization responses in glomus cells to change observed in freshly isolated adrenal chromaffin and cultured PC12 cells exposed tot he same treatments. The effects of hypoxic acclimatization on nitric oxide neuromodulation of carotid body function and glomus cell ion channel activity will be quantified. We will determine whether the stimulation of carotid body function by glutamate and inhibition by arginine and lysine is exerted through action on membrane receptors, or through direct physicochemical properties of the amino acids, and whether the modulation is affected by hypoxic acclimatization. We will also study the role of intracellular glomus cell calcium stores on chemoreception using blockers and agonists of ryanodine and inositol triphosphate receptors, before and after acclimatization. These studies will help define the physiological basis for carotid body adaptation to chronic hypoxia in health and disease.