LONG-TERM MODULATION OF INWARD CURRENTS IN O-2 CHEMORECEPTORS BY CHRONIC HYPOXIA AND CYCLIC-AMP IN-VITRO

In mammals, ventilatory acclimatization to hypoxia is associated with an enhanced chemosensitivity of the O-2- sensing carotid body, resulti ng in an increased respiratory drive. To test whether this sensitizati on involves long-term modulation of ion channel function in endogenous O-2 chemoreceptors, i.e., type 1 cells, we exposed cultures of dissoc iated rat carotid body to chronic hypoxia (6% O-2) for 12 weeks, befor e monitoring the electrophysiological properties of type 1 cells using whole-cell, perforated patch recording. Chronic hypoxia augmented vol tage-dependent inward Na+ and Ca2+ currents in type 1 cells, without s ignificant changes in voltage dependence of activation or steady-state inactivation. However, after normalizing for the concomitant increase in cell size, indicated by the whole-cell capacitance, only the Na+ c urrent density was significantly enhanced. The Na+ current was sensiti ve to tetrodotoxin (TTX; 0.5-1 mu M) or choline substitution, whereas most of the Ca2+ current was sensitive to the L-type calcium channel b locker, nifedipine (10 mu M). Several of these effects of hypoxia were mimicked qualitatively by growing normoxic cultures in the presence o f agents that elevate intracellular cyclic AMP, including dibutyryl cA MP (db-cAMP; 200 mu M-1 mM) and forskolin (10 mu M); treatment with si milar concentrations of dibutyryl cyclic GMP was ineffective, Na+ chan nel induction by db-cAMP was abolished by the protein synthesis inhibi tor, cycloheximide (90-180 mu M). In current-clamp mode, these altered chemoreceptors had typical resting potentials of similar to -55 mV, a nd following depolarization often fired multiple spikes that appeared to consist of both short-duration Na+ and long-duration Ca2+ component s. We propose that chronic hypoxia, acting in part through cAMP-depend ent pathways, increases electrical excitability and calcium mobilizati on in type 1 cells, and these adaptations may help enhance chemosensit ivity during hypoxic acclimatization.