DIFFERENT EFFECTS ON [H-3]NORADRENALINE UPTAKE OF THE ACONITUM ALKALOIDS ACONITINE, 3-ACETYLACONITINE, LAPPACONITINE, AND N-DESACETYLLAPPACONITINE IN RAT HIPPOCAMPUS

The effect of the Aconitum alkaloids aconitine, 3-acetylaconitine, lap paconitine, and N-desacetyllappaconitine to inhibit [H-3]noradrenaline uptake was investigated in rat hippocampal synaptosomes. Aconitine an d 3-acetylaconitine, which are known to activate sodium channels, had comparable inhibitory potencies and yielded K-i(inhibitor constant) va lues of 230+/-66 nM and 316+/-96 nM, respectively;ln contrast, lappaco nitine and N-desacetyllappaconitine failed to inhibit [H-3]noradrenali ne uptake. When either lappaconitine or N-desacetyllappaconitine was a pplied in combination with aconitine, [H-3]noradrenaline uptake was no t affected. The sodium channel blocker tetrodotoxin enhanced [H-3]nora drenaline uptake, whereas uptake was completely blocked in sodium-free incubation medium. The inhibitory action of aconitine and 3-acetylaco nitine on [H-3]noradrenaline uptake was blocked by addition of tetrodo toxin. Patch clamp studies performed on cultured rat hippocampal neuro ns revealed an inhibitory action of lappaconitine and N-desacetyllappa conitine on whole cell sodium currents. It is concluded that the block ade of [H-3]noradrenaline uptake evoked by aconitine and 3-acetylaconi tine is mediated indirectly by an increased sodium concentration in th e synaptosomes. (C) 1998 Elsevier Science Inc.