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Blockade by sigma site ligands of high voltage‐activated Ca 2+ channels in rat and mouse cultured hippocampal pyramidal neurones
Author(s) -
Church John,
Fletcher Elizabeth J.
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb15929.x
Subject(s) - hippocampal formation , chemistry , ifenprodil , nifedipine , dextrorphan , stereochemistry , voltage dependent calcium channel , biophysics , endocrinology , calcium , biochemistry , antagonist , receptor , biology , organic chemistry
1 The effects of a series of structurally‐dissimilar σ site ligands were examined on high voltage‐activated Ca 2+ channel activity in two preparations of cultured hippocampal pyramidal neurones. 2 In mouse hippocampal neurones under whole‐cell voltage‐clamp, voltage‐activated Ca 2+ channel currents carried by barium ions ( I Ba ) were reduced with the rank order (IC 50 values in μ m ): 1S,2R‐(–)‐ cis ‐ N ‐methyl‐ N ‐[2‐(3,4‐dichlorophenyl)ethyl]‐2‐(1‐pyrrolidinyl)cyclohexylamine (7.8) > rimcazole (13) > haloperidol (16)>ifenprodil (18)>opipramol (32)>carbetapentane (40)=1‐benzylspiro[1,2,3,4‐tetrahy‐dronaphthalene‐1,4‐piperidine] (42) >caramiphen (47) >dextromethorphan (73). At the highest concentrations tested, the compounds almost abolished I Ba in the absence of any other pharmacological agent. 3 The current‐voltage characteristics of the whole‐cell I Ba were unaffected by the test compounds. The drug‐induced block was rapid in onset and offset, with the exceptions of carbetapentane and caramiphen where full block was achieved only after two to three voltage‐activated currents and was associated with an apparent increase in the rate of inactivation of I Ba4 In rat hippocampal neurones loaded with the Ca 2+ ‐sensitive dye Fura‐2, rises in intracellular free Ca 2+ concentration evoked by transient exposure to 50 mM K + ‐containing medium, either in the absence or in the presence of 10 μ m nifedipine (to block L‐type high voltage‐activated Ca 2+ channels), were also reversibly attenuated by the σ ligands. The rank order potencies for the compounds in these experimental paradigms were similar to that observed for blockade of I Ba in the electrophysiological studies. 5 These results indicate that, at micromolar concentrations, the compounds tested block multiple subtypes of high voltage‐activated Ca 2+ channels. These actions, which do not appear to be mediated by high‐affinity σ binding sites, may play a role in some of the functional effects previously described for the compounds.