Chronic hypoxia enhances the secretory response of rat phaeochromocytoma cells to acute hypoxia.

1. Amperometric recordings were made from individual phaeochromocytoma (PC12) cells using carbon fibre microelectrodes to investigate the effects of chronic hypoxia (10% O2) on the secretory responses evoked by acute hypoxia. 2. Exposure to chronic hypoxia for 21-26 h increased the frequency of exocytotic events evoked in response to acute hypoxia (PO2 ca 10-60 mmHg). 3. Chronic hypoxia increased the value of Q1/3, determined by the integration of amperometric events, indicating an increase in quantal size: this reflects either an increase in vesicular dimensions or vesicular catecholamine concentration. 4. Exocytotic frequency evoked by bath application of tetraethylammonium (1-10 mM) was significantly enhanced following chronic hypoxia. 5. In both control and chronically hypoxic PC12 cells, exocytosis in response to acute hypoxia was completely abolished in Ca2+-free solutions. Cd2+ (200 microM) completely inhibited exocytosis from control cells, but left a significant residual release in chronically hypoxic PC12 cells. 6. The Cd2+-resistant release evoked by acute hypoxia in chronically hypoxic PC12 cells was inhibited by inorganic ions (0.01-10 mM) in a potency order of La3+ > Gd3+ > Zn2+. Ni2+ (10 mM) was without effect. 7. Our results suggest that chronic hypoxia enhances the secretory response of PC12 cells in part by increasing the depolarization mediated by an oxygen-sensitive K+ channel. In addition, acute hypoxia activates a Cd2+-resistant Ca2+ influx pathway in chronically hypoxic PC12 cells.