Effects of the Aconitum alkaloid mesaconitine in rat hippocampal slices and the involvement of alpha- and beta-adrenoceptors.
1 The effects of mesaconitine, the main alkaloid contained in Aconiti tuber, were investigated by use of extracellular recordings of stimulus-evoked population spikes and field excitatory postsynaptic potentials (e.p.s.ps) in the CA1 region of rat hippocampal slices. 2 At a concentration of 10 nM, mesaconitine evoked excitations, which were manifested as an increase in the amplitude of the orthodromic spike and the appearance of multiple spikes following the first postsynaptic spike, without affecting the magnitude of paired-pulse facilitation. The increase in spike amplitude was persistent and was not reversed by up to 90 min of washout. At concentrations of 30 and 100 nM, the alkaloid produced a biphasic effect, that is an excitation followed by an inhibition without having any effect upon the field e.p.s.p. At concentrations above 100 nM, mesaconitine suppressed the orthodromic population spike and the field e.p.s.p. 3 The excitatory effect was also observed when electrical stimulation was stopped completely during the application of mesaconitine (10 nM) and during the first 15 min of washout. 4 The enhancement of the population spike and the appearance of multiple spikes induced by mesaconitine (10-100 nM) were blocked by pretreatment with the beta-adrenoceptor antagonists propranolol (1 microM) and timolol (1 microM), whereas the inhibitory effect was blocked by the alpha-adrenoceptor antagonists yohimbine (1 microM) and phentolamine (10 microM). However, when the beta-adrenoceptor antagonist timolol was added 10 min after the application of mesaconitine, it failed to block the long-lasting enhancement of the spike amplitude and the appearance of multiple population spikes. 5 Application of the selective beta-adrenoceptor agonist isoprenaline (500 nM) to the hippocampal slices induced an increase in the amplitude of the orthodromic population spike and elicited 2-3 additional spikes. Mesaconitine (10 nM) did not further potentiate this enhancement of the spike amplitude when added after a 15 min pretreatment with isoprenaline. 6 Perfusion of forskolin, which directly activates adenylate cyclase, enhanced the population spike. Mesaconitine had no additional effect when applied after pretreatment with forskolin. 7 It is concluded that the excitatory effects evoked by lower concentrations of the plant alkaloid mesaconitine are mediated by stimulation of beta-adrenoceptors and the consequent activation of intracellular processes which lead to the long-lasting changes in excitability.
Ameri
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Department of Pharmacy and Pharmacology of Natural Compounds, University of Ulm, Germany.
D000157:Aconitine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000648:ultrastructure*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*
D000317:Adrenergic alpha-Antagonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; C019470:mesaconitine; D007545:Isoproterenol; D000157:Aconitine