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 leading to a permanent activation of the channel. 6-Benzoylheteratisine is a plant alkaloid which is structurally related with aconitine. The aim of the present study was to investigate the interaction of aconitine and 6-benzoylheteratisine in the rat hippocampus. The experiments were carried out as extracellular recordings of stimulus evoked population spikes and field excitatory postsynaptic potential (EPSP) in rat hippocampal slices. Aconitine (10-100 nM) exerted a concentration-dependent decrease in the amplitude of the 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 spike 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 not capable to antagonize the aconitine action. 6-Benzoylheteratisine shifted the input-output relationship of the presynaptic fiber spike as function of the stimulation intensity and the input-output relationship of the field EPSP as function of the presynaptic fiber spike to the right. Thus, electrophysiologically this alkaloid seems to inhibit predominantly the excitability of the afferent fibres and, in consequence, neurotransmission between Schaffer collaterals and the CA1 neurons, thereby suppressing the firing of the latter. Spontaneously occurring epileptiform activity in area CA3 elicited by omission of Mg2+ and elevation of K+ was attenuated by 6-benzoylheteratisine (1 and 10 mu M). Patch clamp studies performed on cultured rat hippocampal pyramidal cells revealed an inhibitory action of 6-benzoylheteratisine on whole cell Na+ currents. It is concluded that the inhibitory and antiepileptiform effect of ajacine and lappaconitine is mediated by an inhibition of the voltage-dependent Na+ channel which might be important for filtering high frequency bursts of action potentials characteristic for epileptiform 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.