Effect of benzodiazepine ligands on Ca2+ channel currents in Xenopus oocytes injected with rat heart RNA.
Voltage-dependent Ca2+ channel (VDCC) currents have been measured in Xenopus oocytes injected with heart RNA purified from 7 day old rats, using voltage clamp technique. The currents were evoked by depolarizing voltage steps, using Ba2+ as charge carrier. Electrophysiological analysis of the current revealed two components: a slow, L-type, dihydropyridine (DHP)-sensitive current and a transient, DHP-insensitive, current. The benzodiazepine (BZ) ligands diazepam and Ro5-4864 decreased the current with micromolar affinity, with potency order of Ro5-4864 greater than diazepam greater than clonazepam. The central antagonist Ro15-1788 did not interfere with the effect of these drugs, thus excluding the possible involvement of the "central type" receptor. The slow current that was increased about 3 fold in the presence of 0.5 microM Bay K 8644, was less potentiated when previously treated with Ro5-4864 or diazepam. Current-voltage relation of the peak inward current and the steady state activation curve showed a small shift towards negative potentials in the presence of 50 microM diazepam. It is concluded that the benzodiazepine ligands block DHP-sensitive voltage dependent Ca2+ channels with a very marginal effect on the transient, DHP-insensitive current. Also it is emphasized that Xenopus oocytes can serve as a useful model system to study the pharmacology of these important drugs on cardiac Ca2+ channels.
Gershon
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Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel.
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001464:Barium / Q000378:metabolism; D001569:Benzodiazepines / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D002998:Clonazepam / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005260:Female; D009206:Myocardium / Q000737:chemistry*; D009865:Oocytes; D012313:RNA / Q000235:genetics*; D051381:Rats; D014982:Xenopus laevis
D001570:Benzodiazepinones; D015220:Calcium Channels; D001569:Benzodiazepines; D001464:Barium; C028513:4'-chlorodiazepam; D002998:Clonazepam; D012313:RNA; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D003975:Diazepam