Immediate and long-term responses of the carotid body to high altitude.

High altitude and the decreased environmental oxygen pressure have both immediate and chronic effects on the carotid body. An immediate effect is to limit the oxygen available for mitochondrial oxidative phosphorylation, and this leads to increased activity on the afferent nerves leading to the brain. In the isolated carotid body preparation, the afferent nerve activity depends on the ratio of carbon monoxide (CO), an inhibitor of respiratory chain function, to oxygen. The CO-induced increase in afferent neural activity is reversed by light, and the wavelength dependence of this reversal shows that the site of CO (and therefore oxygen) interaction is cytochrome a3 of the mitochondrial respiratory chain. Thus, primary sensing of ambient oxygen pressure is through the oxygen dependence of mitochondrial oxidative phosphorylation. The conductance of ion channels in the cellular membranes may also be sensitive to oxygen pressure and, through this, modulate the sensitivity to oxygen pressure. Longer-term exposure to high altitude results in progressive changes in the carotid body that involve several mechanisms, including cellular energy metabolism and hypoxia inducible factor-1alpha (HIF-1alpha). These changes begin within minutes of exposure, but progress such that chronic exposure results in morphological and biochemical alterations in the carotid body, including enlarged cells, increased catecholamine levels, altered cellular appearance, and others. In the chronically adapted carotid body, responses to acute changes in oxygen pressure are enhanced. The adaptive changes due to chronic hypoxia are largely reversed upon return to lower altitudes.