POTASSIUM CHANNEL ACTIVATORS COUNTERACT ANOXIC HYPEREXCITABILITY BUT NOT 4-AMINOPYRIDINE-INDUCED EPILEPTIFORM ACTIVITY IN THE RAT HIPPOCAMPAL SLICE

The K+ channel activators diazoxide and cromakalim were investigated f or effects on 4-aminopyridine (4AP)-induced epileptiform activity in a dult rat hippocampal slices maintained in vitro. Under normal conditio ns of oxygenation, 4AP (50 mu M) induced two types of field potentials in extracellular recordings from the CA3 stratum radiatum (apical den dritic region): epileptiform interictal discharge-like events occurrin g at a frequency of 0.75 +/- 0.36 Hz and long-lasting negative-going p otentials mediated by GABA receptor activation that occurred at 0.03 /- 0.01 Hz (n = 36 slices). Neither diazoxide (0.65-1.3 mM, n = 21 sli ces) nor cromakalim (50-200 mu M, n = 6 slices) altered these two type s of discharge. Brief periods of anoxia (4-6 min) reduced the frequenc y of the 4AP-induced interictal-like events (from 0.75 +/- 0.36 Hz to 0.19 +/- 0.15 Hz, n = 20 slices). In 45% of the experiments, the depre ssant effect of anoxia was preceded by a period of hyperexcitability c onsisting of a transient (36.1 +/- 12.9 sec) increase in the frequency of interictal-like events riding on a negative-going DC shift (n = 9 slices). Both responses to anoxia were reversible upon reoxygenation. In contrast, the rate of occurrence of the GABA-mediated potentials wa s unaffected by the anoxic episodes. Perfusion with cromakalim (n = 4 slices) or diazoxide (n = 5 slices) abolished the initial period of hy perexcitability produced by O-2 deprivation but did not alter the subs equent depression of activity. Our experiments indicate that the K+ ch annel activators can prevent the initial hyperexcitability produced by anoxia, but do not influence 4AP-induced epileptiform activity in nor moxic conditions. These findings suggest that K+ channel opener drugs might be useful in the treatment of seizures occurring in the setting of status epilepticus or cerebrovascular disease.