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.