We examined the effects of hypoxia on the release of serotonin (5-HT) from intact neuroepithelial body cells (NEB), presumed airway chemoreceptors, in rabbit lung slices, using amperometry with carbon fibre microelectrodes. Under normoxia (P(O2) ~155 mmHg; 1 mmHg approximately 133 Pa), most NEB cells did not exhibit detectable secretory activity; however, hypoxia elicited a dose-dependent (P(O2) range 95-18 mmHg), tetrodotoxin (TTX)-sensitive stimulation of spike-like exocytotic events, indicative of vesicular amine release. High extracellular K(+) (50 mM) induced a secretory response similar to that elicited by severe hypoxia. Exocytosis was stimulated in normoxic NEB cells after exposure to tetraethylammonium (20 mM) or 4-aminopyridine (2 mM). Hypoxia-induced secretion was abolished by the non-specific Ca(2+) channel blocker Cd(2+) (100 microM). Secretion was also largely inhibited by the L-type Ca(2+) channel blocker nifedipine (2 microM), but not by the N-type Ca(2+) channel blocker omega-conotoxin GVIA (1 microM). The 5-HT(3) receptor blocker ICS 205 930 also inhibited secretion from NEB cells under hypoxia. These results suggest that hypoxia stimulates 5-HT secretion from intact NEBs via inhibition of K(+) channels, augmentation of Na(+)-dependent action potentials and calcium entry through L-type Ca(2+) channels, as well as by positive feedback activation of 5-HT(3) autoreceptors.