Interaction of the structurally related Aconitum alkaloids, aconitine and 6-benzyolheteratisine, in the rat hippocampus

Aconitine is a highly toxic diterpenoid alkaloid occurring in plants of the Aconitum genus. Aconitine is known to shift the voltage-dependence of the voltage-dependent Na+ channel towards hyperpolarized direction, thereby lea ding to a permanent activation of the channel. 6-Benzoylheteratisine is a p lant alkaloid which is structurally related with aconitine. The aim of the present study was to investigate the interaction of aconitine and 6-benzoyl heteratisine in the rat hippocampus. The experiments were carried out as ex tracellular recordings of stimulus evoked population spikes and field excit atory postsynaptic potential (EPSP) in rat hippocampal slices. Aconitine (1 0-100 nM) exerted a concentration-dependent decrease in the amplitude of th e orthodromic population spike. When aconitine was applied in presence of 6 -benzoylheteratisine (3 mu M), the concentration-response curve was shifted to the right. Furthermore, the complete suppression of the population spik e evoked by 100 nM aconitine was reversed by 10 mu M 6-benzoylheteratisine. The closely related alkaloid heteratisine (3 and 30 mu M), however, was no t capable to antagonize the aconitine action. 6-Benzoylheteratisine shifted the input-output relationship of the presynaptic fiber spike as function o f the stimulation intensity and the input-output relationship of the field EPSP as function of the presynaptic fiber spike to the right. Thus, electro physiologically this alkaloid seems to inhibit predominantly the excitabili ty of the afferent fibres and, in consequence, neurotransmission between Sc haffer collaterals and the CA1 neurons, thereby suppressing the firing of t he latter. Spontaneously occurring epileptiform activity in area CA3 elicit ed by omission of Mg2+ and elevation of K+ was attenuated by 6-benzoylheter atisine (1 and 10 mu M). Patch clamp studies performed on cultured rat hipp ocampal pyramidal cells revealed an inhibitory action of 6-benzoylheteratis ine on whole cell Na+ currents. It is concluded that the inhibitory and ant iepileptiform effect of ajacine and lappaconitine is mediated by an inhibit ion of the voltage-dependent Na+ channel which might be important for filte ring high frequency bursts of action potentials characteristic for epilepti form activity in the hippocampus. Thus, 6-benzoylheteratisine seems to be a naturally occurring antagonist of the Na+ channel activator aconitine. (C) 1999 Elsevier Science B.V. All rights reserved.