Loss of synaptic transmission and accumulation of extracellular K⁢([K⁢]O) are the key features in ischemic brain damage. Here, we examined the effects of several K⁢channel modulators on the early ischemic changes in population spike (PS) and [K⁢]o in the CA1 pyramidal layer of the rat hippocampal slice using electrophysiological techniques. After onset of anoxic aglycemia (AA), orthodromic field potentials decreased and disappeared in 3.3⁑0.22 min (mean⁑SEM, n=40). The hypoxic injury potential (HIP), a transient recovery of PS appeared at 6.0⁑0.25 min (n=40) in most slices during AA and lasted for 3.3⁑0.43 min. [K⁢]O increased initially at a rate of 0.43 mM/min (Phase 1) and later at a much faster rate (12.45 mM/min, Phase 2). The beginning of Phase 2 was invariably coincided with the disappearance of HIP. Among K⁢ channel modulators tested such as 4-aminopyridine (0.03, 0.3 mM), tetraethylammonium (0.1 mM), NS1619 (0.3∼10 ՌM), niflumic acid (0.1 mM), glibenclamide (40 ՌM), tolbutamide (300 ՌM) and pinacidil (100 ՌM), only 4-aminopyridine (0.3 mM) induced slight increase of [K⁢]O during Phase 1. However, none of the above agents modulated the pattern of Phase 2 in [K⁢]O in response to AA. Taken together, the experimental data suggest that 4-aminopyridine-sensitive K⁢channels, large conductance Ca2⁢-activated K⁢ channels and ATP-sensitive K⁢ channels may not be the major contributors to the sudden increase of [K⁢]O during the early stage of brain ischemia, suggesting the presence of other routes of K⁢efflux during brain ischemia.