SULFONYLUREAS REDUCE THE SLOWLY INACTIVATING D-TYPE OUTWARD CURRENT IN RAT HIPPOCAMPAL-NEURONS

1. Using intracellular recording in hippocampal slices, we have examin ed, in CA3 pyramidal neurons, the effects of sulphonylureas (blockers of ATP-sensitive K+ channels) on the slowly inactivating D-type K+ cur rent (I(D)). 2. In the presence of TTX (1 mum) to block Na+ currents, I(D) had the following characteristics: activation by large depolarizi ng pulses from membrane potentials negative to - 75 mV, slow inactivat ion kinetics, high sensitivity to 4-aminopyridine (4-AP, 3-40 muM), in sensitivity to tetraethylammonium (TEA, 10 mM), Cs+ (3 mM) and carbach ol (50 muM). 3. Applications of glibenclamide (10 muM) did not modify the input conductance of the cell, but reduced the amplitude of I(D) b y 31.2 +/- 5.6 % (n = 16), without altering its voltage dependence and inactivation kinetics. The effects were usually reversible. 4. Gliben clamide also reduced ID in the presence of TEA (10 mM), Cs+ (3 mM) and carbachol (50 muM), to block several K+ currents (I(K), I(C), I(Q), I (M)), as well as kynurenate (1 mM) and bicuculline (10 muM) to block o n-going synaptic currents mediated by activation of non-NMDA (N-methyl -D-aspartate) and GABA (gamma-aminobutyrate)-A receptors, respectively . 5. Comparable depressions of I(D) were produced by two other sulphon ylureas: gliquidone (10 muM), 42.6 +/- 7.9 % (n = 13) and tolbutamide (500 muM), 39.1 +/- 12.8 (n = 8). 6. It is concluded that, in the cent ral nervous system, sulphonylureas can modulate K+ currents which are not generated by ATP-sensitive K+ channels.