Summary:Purpose: BIA 2-093 [(S)-(-)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide] is endowed with an anticonvulsant potency similar to that of carbamazepine (CBZ), but produces less cognitive and motor impairment. This study evaluated whether voltage-gated sodium channels (VGSCs) are a primary locus for the action of BIA 2-093.Methods: We used the whole-cell voltage-clamp technique in the mouse neuroblastoma cell line N1E-115 to investigate the effects of BIA 2-093 and CBZ on VGSCs, displacement of Conclusions: BIA 2-093, like CBZ, inhibits sodium currents in a voltage-dependent way by an interaction predominantly with the inactivated state of the channel and interacts with neurotoxin receptor site 2, but not with receptor site 1. BIA 2-093 displayed a potency blocking VGSCs similar to that of CBZ.
The effects of the cholinoceptor agonist, carbachol (CCh), were examined in the rat hippocampal slice preparation. Intracellular recordings from CA 1 pyramidal neurones revealed that CCh (1-3/~M) inhibited excitatory postsynaptic responses evoked by stimulation of the Schaffer collateral/commissural pathway while, at the same time, direct excitability was enhanced. Extracellularly, CCh produced a concentrationdependent reduction of the amplitude of the field excitatory postsynaptic potential (field EPSP) recorded in the CAI apical dendritic region. The muscarinic receptor antagonist, pirenzepine, competitively antagonized the effects of CCh on the field EPSP with a pA2 of 7.4. These results confirm earlier reports of a presynaptic inhibitory action of CCh in the hippocampal CAI region and provide strong evidence that this effect is mediated by muscarinic receptors of the Mt subtype.The classification of muscarinic receptors into two broad categories on the basis of their high (M0 and low (M2) affinities for the antagonist, pirenzepine [9], has prompted a number of attempts to establish the subtypes mediating the electrophysiological responses to muscarinic agonists throughout the brain [4-6, 14-16, 19]. In hippocampal CA I pyramidal neurones, both the membrane depolarization and blockade of IAHp induced by carbachol (CCh) have been attributed to an action at M1 receptors, whereas inhibition of the M-current may result from M2 receptor activation [4]. In addition to these postsynaptic effects, muscarinic agonists can also reduce the synaptically-evoked excitation of CA 1 neurones by a presynaptic mechanism [11,18]. Unfortunately, attempts to classify this latter response in terms of receptor subtype have yielded conflicting reports: both M2 [4] and Mi [16] receptors have been implicated. However, since neither of these earlier studies employed formal quantitative pharmacological procedures, conclusions from them must remain tentative. We
Extracellular recording techniques have been used in the guinea pig hippocampal slice preparation to investigate the electrophysiological actions of the organophosphate (OP) anticholinesterase soman. When applied at a concentration of 100 nM, soman induced epileptiform activity in the CA1 region in approximately 75% of slices. This effect was mimicked by the anticholinesterases paraoxon (1 and 3 M), physostigmine (30 M), and neostigmine (30 M), thus providing indirect evidence that the epileptiform response was mediated by elevated acetylcholine levels. Soman-induced bursting was inhibited by the muscarinic receptor antagonists atropine (concentrations tested, 0
1 The effects of imidazopyrazine derivative, SCA40, on the activity of single large conductance, Ca2+-activated K+ (BKCa) channels in inside-out and outside-out patches from bovine tracheal smooth muscle (BTSM) BKCa channels when applied to either inside-out or outside-out BTSM patches, thus confirming that these compounds are activators of the BKCa channel in this preparation. 4 SCA40 (0.1 -10 pM) had no effect on the activity of BKCa channels when applied to either inside-out or outside-out patches which subsequently responded to the application of NS 004 (10-20 pM).
5It is concluded that SCA40 does not have a direct effect on BKca channel activity in BTSM patches and that the previously reported relaxant action of SCA40 on tracheal smooth muscle is unlikely to be mediated by this mechanism.
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