Effects of monocarboxylic acid‐derived Cl⁻ channel blockers on depolarization‐activated potassium currents in rat ventricular myocytes

Abstract

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.

Fenamates block gap junction coupling and potentiate BKCa channels in guinea pig arteriolar cells

“…5). In this regard, a previous study also reported that NFA and a structure-related Cl-channel blocker 5-Nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) potentiated depolarization-activated potassium currents in rat ventricular myocytes (Zhou et al, 2007). Wu et al (2001)(Wu et al, 2001) also found that FFA activated BK Ca channels in osteoblast-like MG-63 cells.…”

Cardiomyocytes with disrupted CFTR function require CaMKII and Ca2+‐activated Cl− channel activity to maintain contraction rate

“…Additionally, in bovine pulmonary artery endothelial cells (Wei et al 2001), Xenopus oocytes (Kunzelmann et al 1997) and mouse parotid acinar cells (Perez‐Cornejo & Arreola, 2004), expression of CFTR leads to a negative regulation of CaCC. While niflumic acid is a well‐documented inhibitor of CaCC (Hartzell et al 2005), it is not specific and can also affect CFTR (Scott‐Ward et al 2004) and K + channels (Wang et al 1997; Zhou et al 2007). Although we cannot rule out effects on non‐CFTR targets, the effects of niflumic acid on the contraction rate of cardiomyocytes from CFTR KO mice make us confident that our results are not due to additional effects on CFTR.…”

The effect of drugs with ion channel‐blocking activity on the early embryonic rat heart

“…However, it is not a I Kr /hERG inhibitor but actually enhances hERG currents (Malykhina et al, 2002). It also inhibits I CaL and sodium channels (Zhou et al, 2007) and alters the gating of HCN2 pacemaker channels (Cheng and Sanguinetti, 2009). …”