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Effects of monocarboxylic acid‐derived Cl − channel blockers on depolarization‐activated potassium currents in rat ventricular myocytes
Author(s) -
Zhou ShiSheng,
Zhang LiBin,
Sun WuPing,
Xiao FuCheng,
Zhou YiMing,
Li YaJie,
Li DongLiang
Publication year - 2007
Publication title -
experimental physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.925
H-Index - 101
eISSN - 1469-445X
pISSN - 0958-0670
DOI - 10.1113/expphysiol.2007.037069
Subject(s) - genistein , depolarization , chemistry , niflumic acid , patch clamp , channel blocker , potassium channel , potassium channel blocker , myocyte , cardiac transient outward potassium current , medicine , protein kinase c , pharmacology , endocrinology , biophysics , kinase , biochemistry , biology , receptor , organic chemistry , calcium
The effects of monocarboxylic acid‐derived Cl − channel blockers on cardiac depolarization‐activated K + currents were investigated. Membrane currents in rat ventricular myocytes were recorded using the whole‐cell configuration of the patch‐clamp technique. 5‐Nitro‐2‐(3‐phenylpropylamino)‐benzoic acid (NPPB) and niflumic acid (NFA) induced an outward current at 0 mV. Both NPPB and NFA failed to induce any current when used intracellularly or after K + in the bath and pipette solutions was replaced by equimolar Cs + . Voltage pulse protocols revealed that NPPB and NFA enhanced the steady‐state K + current but inhibited the transient outward K + current. Genistein, a tyrosine kinase (PTK) inhibitor, inhibited NPPB‐ and NFA‐induced outward current. Another PTK inhibitor, lavendustin A, produced a comparable effect. In contrast, the inactive analogue of genistein, daidzein, was ineffective. Orthovanadate, a tyrosine phosphatase inhibitor, markedly slowed the deactivation of the outward current induced by NPPB and NFA. The protein kinase A (PKA) inhibitor H‐89 inhibited NPPB‐induced outward current at 0 mV. In contrast, the protein kinase C (PKC) inhibitor H‐7 was without significant effect on the action of NPPB. Pretreatment of the myocytes with genistein or H‐89 prevented the enhancing effect of NPPB. Increasing intracellular Cl − from 22 to 132 m m slightly reduced NPPB‐induced outward current at 0 mV. These results demonstrate that the monocarboxylic acid‐derived Cl − channel blockers NPPB and NFA enhance cardiac steady‐state K + current, and suggest that the enhancing effect of the Cl − channel blockers is mediated by stimulation of PKA and PTK signalling pathways.