Effects of monocarboxylic acid-derived Cl- channel blockers on depolarization-activated potassium currents in rat ventricular myocytes.
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 mm 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.
Zhou
Shi-Sheng
SS
Institute of Basic Medical Sciences, Medical College, Dalian University, Dalian 116622, China.
Zhang
Li-Bin
LB
Sun
Wu-Ping
WP
Xiao
Fu-Cheng
FC
Zhou
Yi-Ming
YM
Li
Ya-Jie
YJ
Li
Dong-Liang
DL
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D018118:Chloride Channels / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D009544:Niflumic Acid / Q000494:pharmacology; D009579:Nitrobenzoates / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010636:Phenols / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D014638:Vanadates / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D018118:Chloride Channels; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D009579:Nitrobenzoates; D010636:Phenols; D015221:Potassium Channels; D013449:Sulfonamides; C058176:5-nitro-2-(3-phenylpropylamino)benzoic acid; D014638:Vanadates; C062898:lavendustin A; D009544:Niflumic Acid; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D019833:Genistein; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide