Differential effects of the neuroprotectant lubeluzole on bovine and mouse chromaffin cell calcium channel subtypes

1 The effects of lubeluzole (a neuroprotective benzothiazole derivative) and its (−) enantiomer R91154 on whole‐cell currents through Ca2+ channels, with 10 mM Ba2+ as charge carrier (IBa), have been studied in bovine and mouse voltage‐clamped adrenal chromaffin cells. Currents generated by applying...

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Published in:British journal of pharmacology 1997-09, Vol.122 (2), p.275-285
Main Authors: Hernández‐Guijo, Jesús M., Gandía, Luis, De Pascual, Ricardo, García, Antonio G.
Format: Article
Language:English
Subjects:
Animals
Barium - pharmacology
Biological and medical sciences
calcium channel
Calcium Channel Blockers - pharmacology
Cattle
chromaffin cell
Chromaffin Cells - drug effects
Chromaffin Cells - physiology
Lubeluzole
Medical sciences
Mice
Neuropharmacology
Neuroprotective agent
Neuroprotective Agents - pharmacology
Patch-Clamp Techniques
Pharmacology. Drug treatments
Piperidines - pharmacology
R91154
Stereoisomerism
Thiazoles - pharmacology
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Summary:1 The effects of lubeluzole (a neuroprotective benzothiazole derivative) and its (−) enantiomer R91154 on whole‐cell currents through Ca2+ channels, with 10 mM Ba2+ as charge carrier (IBa), have been studied in bovine and mouse voltage‐clamped adrenal chromaffin cells. Currents generated by applying 50 ms depolarizing test pulses to 0 mV, from a holding potential of −80 mV, at 10 s intervals had an average magnitude of 1 nA. 2 Lubeluzole and R91154 blocked the peak IBa of bovine chromaffin cells in a time and concentration‐dependent manner; their IC50s were 1.94 μM for lubeluzole and 2.54 μM for R91154. In a current‐voltage protocol, lubeluzole (3 μM) inhibited peak IBa at all test potentials. However, no obvious shifts of the I‐V curve were detected. 3 After 10 min exposure to 3 μM lubeluzole, the late current (measured at the end of the pulse) was inhibited more than the peak current. Upon wash out of the drug, the inactivation reversed first and then the peak current recovered. 4 Blockade of peak current was greater at more depolarizing holding potentials (i.e. 35% at −110 mV and 87% at −50 mV, after 10 min superfusion with lubeluzole). Inactivation of the current was pronounced at −110 mV, decreased at −80 mV and did not occur at −50 mV. 5 Intracellular dialysis of bovine voltage‐clamped chromaffin cells with 3 μM lubeluzole caused neither blockade nor inactivation of IBa. The external application of 3 μM lubeluzole to those dialysed cells produced inhibition as well as inactivation of IBa. 6 The effects of lubeluzole (3 μM) on IBa in mouse chromaffin cells were similar to those in bovine chromaffin cells. At −80 mV holding potential, a pronounced inactivation of the current led to greater blockade of the late IBa (66%) as compared with peak IBa (46% after 10 min superfusion with lubeluzole). 7 In mouse chromaffin cells approximately half of the whole‐cell IBa was sensitive to 3 μM nifedipine (L‐type Ca2+ channels) and the other half to 3 μM ω‐conotoxin MVIIC (non‐L‐type Ca2+ channels). In ω‐conotoxin MVIIC‐treated cells, 3 μM lubeluzole caused little blockade and inactivation of IBa. However in nifedipine‐treated cells, lubeluzole caused a pronounced blockade and inactivation of IBa that reversed upon wash out of the compound. 8 The results are compatible with the idea that lubeluzole preferentially blocks non‐L‐types of voltage‐dependent Ca2+ channels expressed by bovine and mouse chromaffin cells. The higher concentrations of the compound also block
ISSN:0007-1188
1476-5381
DOI:10.1038/sj.bjp.0701364