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Br J Pharmacol
2002 May 01;1362:183-92. doi: 10.1038/sj.bjp.0704699.
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Effects of benzothiazepines on human neuronal nicotinic receptors expressed in Xenopus oocytes.
Sala F, Mulet J, Valor LM, Criado M, Sala S.
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1. We have investigated the effect of diltiazem and its newly synthesized derivative (+,-)-trans-3-acetoxy-8-chloro-2,3-dihydro-5[2-diisopropylamine)ethyl]-2-(4-methoxyphenyl)-1,5-benzothiazepin-4-(5H)-ona hydrochloride (JAC-65) on several recombinant human neuronal nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes. 2. At 3 microM, both drugs have little effect on the maximal currents evoked by brief pulses of acetylcholine (ACh) in five subtypes of nAChRs (alpha7, alpha3beta2, alpha4beta2, alpha3beta4, and alpha4beta4), showing little selectivity among subtypes. 3. However, both drugs accelerate the decay of the ionic currents evoked upon continuous stimulation of ACh, being this effect larger with JAC-65, and in beta4*-nAChRs. Such an effect was dependent on the concentrations of both the drug and of the agonist used, and showed the characteristics of a non-competitive antagonism. 4. We have further investigated the effect of both drugs when combined with submicromolar concentrations of nicotine, such as those present in plasma of cigarette smokers, and found that JAC-65, but not diltiazem, is able to greatly enhance the desensitizing effect of these low concentrations of nicotine, specially in beta4*-nAChRs. 5. Experiments in alpha4beta4-nAChRs failed to show voltage dependence of the action of JAC-65. Moreover, recovery from desensitization followed the same time course regardless of the presence of the drug, suggesting that the main mechanism of action of JAC-65 does not involve open channel block. 6. In summary, both drugs, diltiazem and JAC-65, seem to act through a non-competitive mechanism, accelerating the decay of the ionic currents, being JAC-65 more effective than diltiazem at the concentrations used in beta4*-nAChRs. Thus, the differences between both benzothiazepines when measuring various parameters suggest that their mechanisms of action could be slightly different. This would require further investigation.
Barabino,
An alpha4beta4 nicotinic receptor subtype is present in chick retina: identification, characterization and pharmacological comparison with the transfected alpha4beta4 and alpha6beta4 subtypes.
2001, Pubmed
Barabino,
An alpha4beta4 nicotinic receptor subtype is present in chick retina: identification, characterization and pharmacological comparison with the transfected alpha4beta4 and alpha6beta4 subtypes.
2001,
Pubmed Benowitz,
Nicotine dependence and tolerance in man: pharmacokinetic and pharmacodynamic investigations.
1989,
Pubmed Bohler,
Desensitization of neuronal nicotinic acetylcholine receptors conferred by N-terminal segments of the beta 2 subunit.
2001,
Pubmed
,
Xenbase Boyd,
Multiple actions of substance P that regulate the functional properties of acetylcholine receptors of clonal rat PC12 cells.
1987,
Pubmed Buisson,
Chronic exposure to nicotine upregulates the human (alpha)4((beta)2 nicotinic acetylcholine receptor function.
2001,
Pubmed Buisson,
Open-channel blockers at the human alpha4beta2 neuronal nicotinic acetylcholine receptor.
1998,
Pubmed Chavez-Noriega,
Pharmacological characterization of recombinant human neuronal nicotinic acetylcholine receptors h alpha 2 beta 2, h alpha 2 beta 4, h alpha 3 beta 2, h alpha 3 beta 4, h alpha 4 beta 2, h alpha 4 beta 4 and h alpha 7 expressed in Xenopus oocytes.
1997,
Pubmed
,
Xenbase Colquhoun,
Pharmacology of neuronal nicotinic acetylcholine receptor subtypes.
1997,
Pubmed Cross,
Enhancement by 5-hydroxytryptamine and analogues of desensitization of neuronal and muscle nicotinic receptors expressed in Xenopus oocytes.
1995,
Pubmed
,
Xenbase Dani,
Molecular and cellular aspects of nicotine abuse.
1996,
Pubmed el-Bizri,
Regulation of nicotinic receptors in rat brain following quasi-irreversible nicotinic blockade by chlorisondamine and chronic treatment with nicotine.
1994,
Pubmed Fenster,
Upregulation of surface alpha4beta2 nicotinic receptors is initiated by receptor desensitization after chronic exposure to nicotine.
1999,
Pubmed
,
Xenbase Fenster,
Regulation of alpha4beta2 nicotinic receptor desensitization by calcium and protein kinase C.
1999,
Pubmed
,
Xenbase Fenster,
Influence of subunit composition on desensitization of neuronal acetylcholine receptors at low concentrations of nicotine.
1997,
Pubmed
,
Xenbase Gandía,
Inhibition of nicotinic receptor-mediated responses in bovine chromaffin cells by diltiazem.
1996,
Pubmed Giniatullin,
Rapid relief of block by mecamylamine of neuronal nicotinic acetylcholine receptors of rat chromaffin cells in vitro: an electrophysiological and modeling study.
2000,
Pubmed Gopalakrishnan,
Regulation of human alpha4beta2 neuronal nicotinic acetylcholine receptors by cholinergic channel ligands and second messenger pathways.
1997,
Pubmed Hargreaves,
Direct inhibition of 5-hydroxytryptamine3 receptors by antagonists of L-type Ca2+ channels.
1996,
Pubmed Herrero,
Differential blockade of rat alpha3beta4 and alpha7 neuronal nicotinic receptors by omega-conotoxin MVIIC, omega-conotoxin GVIA and diltiazem.
1999,
Pubmed
,
Xenbase Houlihan,
Effects of diltiazem on human nicotinic acetylcholine and GABA(A) receptors.
2000,
Pubmed
,
Xenbase Hsu,
Sustained nicotine exposure differentially affects alpha 3 beta 2 and alpha 4 beta 2 neuronal nicotinic receptors expressed in Xenopus oocytes.
1996,
Pubmed
,
Xenbase Hsu,
Nicotine enhances the cyclic AMP-dependent protein kinase-mediated phosphorylation of alpha4 subunits of neuronal nicotinic receptors.
1997,
Pubmed
,
Xenbase Jones,
Nicotinic receptors in the brain: correlating physiology with function.
1999,
Pubmed Krieg,
Functional messenger RNAs are produced by SP6 in vitro transcription of cloned cDNAs.
1984,
Pubmed
,
Xenbase McGehee,
Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors.
1995,
Pubmed Molinari,
Up-regulation of human alpha7 nicotinic receptors by chronic treatment with activator and antagonist ligands.
1998,
Pubmed Paterson,
Neuronal nicotinic receptors in the human brain.
2000,
Pubmed
,
Xenbase Peng,
Human alpha 7 acetylcholine receptor: cloning of the alpha 7 subunit from the SH-SY5Y cell line and determination of pharmacological properties of native receptors and functional alpha 7 homomers expressed in Xenopus oocytes.
1994,
Pubmed
,
Xenbase Pidoplichko,
Nicotine activates and desensitizes midbrain dopamine neurons.
1997,
Pubmed Reitstetter,
Dependence of nicotinic acetylcholine receptor recovery from desensitization on the duration of agonist exposure.
1999,
Pubmed Sargent,
The diversity of neuronal nicotinic acetylcholine receptors.
1993,
Pubmed Shafaee,
Pharmacological similarities between native brain and heterologously expressed alpha4beta2 nicotinic receptors.
1999,
Pubmed
,
Xenbase Sivilotti,
Recombinant nicotinic receptors, expressed in Xenopus oocytes, do not resemble native rat sympathetic ganglion receptors in single-channel behaviour.
1997,
Pubmed
,
Xenbase Stauderman,
Characterization of human recombinant neuronal nicotinic acetylcholine receptor subunit combinations alpha2beta4, alpha3beta4 and alpha4beta4 stably expressed in HEK293 cells.
1998,
Pubmed Stone,
Effects of nicotinic antagonists on ocular growth and experimental myopia.
2001,
Pubmed Stühmer,
Electrophysiologic recordings from Xenopus oocytes.
1998,
Pubmed
,
Xenbase Valenta,
Peptide modulation of ACh receptor desensitization controls neurotransmitter release from chicken sympathetic neurons.
1993,
Pubmed Valera,
Progesterone modulates a neuronal nicotinic acetylcholine receptor.
1992,
Pubmed
,
Xenbase Yeung,
Steady-state plasma concentrations of diltiazem and its metabolites in patients and healthy volunteers.
1996,
Pubmed
