Dihydropyridines and verapamil inhibit voltage-dependent K+ current in isolated outer hair cells of the guinea pig.
Dihydropyridines and verapamil are widely used as blockers of voltage-dependent Ca++ channels. In this work we show that these compounds can have a direct blocking action on a class of voltage-activated potassium channels. Voltage-dependent whole-cell currents were recorded from isolated guinea-pig outer hair cells (OHCs) under conditions such that the free Ca++ concentration in both the internal and external solutions was minimized. A substantial Ca(++)-independent K+ current was revealed by this procedure. Both conventional K+ and Ca++ channel ligands inhibited this current. The order of potency (in terms of the half inhibitory concentrations (IC50) of channel inhibitors) was: nimodipine (6 microM) > Bay K 8644 (8 microM) > verapamil (11 microM) > 4-aminopyridine (22 microM) > nifedipine (32 microM) > quinine (49 microM) > TEA (10236 microM). Except for verapamil, these channel ligands reduced the size of the K+ currents without much alteration of the time course of the currents. In contrast, verapamil caused a more than 10-fold increase in the apparent inactivation rate of the K+ currents without significantly altering the activation of the currents. The observation that relatively low concentrations of calcium channel ligands can directly inhibit potassium currents in isolated OHCs indicates that caution should be taken when these pharmacological agents are used as tools for studying cochlear hair cell physiology.
Lin
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Kresge Hearing Research Institute, University of Michigan, Ann Arbor 48109, USA. xlin@merle.acns.nwu.edu
Hume
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Nuttall
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D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003051:Cochlea / Q000166:cytology / Q000187:drug effects; D006168:Guinea Pigs; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects* / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology; D009553:Nimodipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D011803:Quinine / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology*
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D026902:Potassium Channel Blockers; D009553:Nimodipine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D011803:Quinine; D015761:4-Aminopyridine; D014700:Verapamil; D009543:Nifedipine