Effect of K+ Channel Blockers on the Alpha 2-adrenoceptor-coupled Regulation of Electrically Evoked Noradrenaline Release in Hippocampus

The question whether presynaptic alpha 2-adrenoceptors regulating noradrenaline release in hippocampus directly couple to tetraethylammonium chloride (TEA) or alpha-dendrotoxin (alpha-DTX)-sensitive K+ channels was investigated. Hippocampal slices, prelabelled with [3H] noradrenaline, were superfused in the presence of (+)-oxaprotiline and electrically stimulated with 4 pulses delivered at 100 Hz, in order to avoid autoinhibition due to released noradrenaline. TEA enhanced the evoked [3H]noradrenaline release in rabbit hippocampus in a concentration-dependent manner, yielding an approximately 4-fold increase at 30 mmol/l, whereas the spontaneous outflow of tritium was only slightly affected at this concentration. The alpha 2-adrenoceptor agonist clonidine, at 10-100 nmol/l inhibited the evoked [3H]noradrenaline release between 77% and 96%. The inhibitory effect of the alpha 2-agonist was distinctly diminished in the presence of 30 mmol/l TEA but was restored in low Ca2+/high Mg2+ buffer. Therefore, the diminution of the alpha 2-agonist effect by TEA observed in experiments with normal Ca2+ can be explained by an increase of the Ca2+ availability for the release process due to the prolongation of action potentials. In rabbit hippocampus alpha-DTX (10-200 nmol/l) did neither affect the evoked release of [3H]noradrenaline nor its alpha 2-agonist-induced modulation. However, in rat hippocampus alpha-DTX significantly increased the evoked transmitter release and diminished the effect of clonidine. Taken together, the present data for the rabbit hippocampus exclude the possibility that activation of presynaptic alpha 2-adrenoceptors inhibits depolarization-evoked [3H]noradrenaline release by inducing an outward K+ current through TEA- or alpha-DTX-sensitive K+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)