Carotid body chemoreceptors are the primary sensory organs that cause ventilation to increase in response to a decrease in PaO2 or pHa. This responsiveness is weak at birth and increases during the first few weeks of life. Although the relationship between afferent sinus nerve activity and PaO2 or pHa is well characterized, the mechanisms of transduction and maturation are not understood. The glomus cell, in apposition to the afferent nerve ending, is the most likely site of transduction since chemosensitivity is ablated following glomus cell destruction. However, results of electrophysiologic studies on glomus cell response to hypoxia have been inconsistent between laboratories and preparations. For instance, opposing evidence exists that glomus cells are electrically excitable and unexcitable and that membrane ionic currents increase and decrease with hypoxia. In order to resolve these issues and understand the basis for chemosensitivity and its developmental change, we propose to employ patch clamp recording and optical measurements of glomus cells which are acutely isolated from rabbits. Our preliminary results have established our ability to harvest, patch-clamp and optically record from glomus cells of adults and newborns. We have demonstrated that hypoxic hypoxia and histotoxic hypoxia cause specific, but opposite, changes in a voltage-dependent outward current expressed in glomus cells, and the response to both agents is absent or reduced in the newborn glomus cell. The following general hypothesis is formulated: Chemotransduction of hypoxia is mediated by an O2 dependent change in a Ca++ binding protein. The following questions will be addressed: 1) What changes occur in sodium, potassium and calcium ionic membrane currents of adult glomus cells in response to hypoxia, increased H+ and decreased energy production? 2) How are intracellular Ca++ and pH regulated in glomus cells and do levels change with hypoxia? 3) What changes account for the maturational increase in carotid body hypoxia sensitivity? The anticipated results from this work will allow us to better understand the mechanisms of chemoreceptor transduction during maturation. This may lead to therapeutic strategies that can alter chemosensitivity and thereby improve treatment of apnea and hypoventilation in the neonate and older subject.
