Disopyramide block of KATP channels is mediated by the pore-forming subunit

doi:10.1016/S0024-3205(00)00486-0

Life Sciences

Volume 66, Issue 17, 17 March 2000, Pages PL245-PL252

https://doi.org/10.1016/S0024-3205(00)00486-0 Get rights and content

Abstract

The class Ia antiarrhythmic agent disopyramide blocks native ATP-sensitive K⁺ (K_ATP) channels at micromolar concentrations. The K_ATP channel is a complex of a pore-forming inwardly rectifying K⁺ channel (Kir6.2) and a sulfonylurea receptor (SUR). The aim of the present study was to further localize the site of action of disopyramide. We have used a C-terminal truncated form of Kir6.2 (Kir6.2Δ26), which — in contrast to Kir6.2 — expresses independently of SUR. Kir6.2Δ26 channels were expressed in African green monkey kidney COS-7 cells, and enhanced green fluorescent protein (EGFP) cDNA was used as a reporter gene. EGFP fluorescence was visualized by a laser scanning confocal microscope. Disopyramide applied to the cytoplasmic membrane surface of inside-out patches inhibited Kir6.2Δ26 channels half-maximally at 7.1 μM (at pH 7.15). Lowering the intracellular pH to 6.5 potentiated the inhibition of Kir6.2Δ26 channels by disopyramide. These observations suggest that disopyramide directly blocks the pore-forming Kir6.2 subunit, in particular at reduced intracellular pH values that occur under cardiac ischaemia.

References (20)

C. Moser et al.
Eur. J. Pharmacol.
(1995)
E. Mukai et al.
Biochem. Biophys. Res. Commun.
(1998)
M. Hiraoka et al.
Am. J. Cardiol.
(1989)
M. Horie et al.
Cardiovasc. Res.
(1992)
B. Wu et al.
Cardiovasc. Res.
(1992)
F.G. De Lorenzi et al.
J. Pharmacol. Exp. Ther.
(1995)
S. Hayashi et al.
Am. J. Physiol.
(1993)
L. Aguilar-Bryan et al.
Physiol. Rev.
(1998)
S.J. Tucker et al.
Nature
(1997)
O.P. Hamill et al.
Pflügers Arch.
(1981)

There are more references available in the full text version of this article.

Cited by (8)

Human ether-a-go-go-related (HERG) gene and ATP-sensitive potassium channels as targets for adverse drug effects
2006, Pharmacology and Therapeutics
Torsades de pointes (TdP) arrhythmia is a potentially fatal form of ventricular arrhythmia that occurs under conditions where cardiac repolarization is delayed (as indicated by prolonged QT intervals from electrocardiographic recordings). A likely mechanism for QT interval prolongation and TdP arrhythmias is blockade of the rapid component of the cardiac delayed rectifier K⁺ current (I_Kr), which is encoded by human ether-a-go-go-related gene (HERG). Over 100 non-cardiovascular drugs have the potential to induce QT interval prolongations in the electrocardiogram (ECG) or TdP arrhythmias. The binding site of most HERG channel blockers is located inside the central cavity of the channel. An evaluation of possible effects on HERG channels during the development of novel drugs is recommended by international guidelines. During cardiac ischaemia activation of ATP-sensitive K⁺ (K_ATP) channels contributes to action potential (AP) shortening which is either cardiotoxic by inducing re-entrant ventricular arrhythmias or cardioprotective by inducing energy-sparing effects or ischaemic preconditioning (IPC). K_ATP channels are formed by an inward-rectifier K⁺ channel (Kir6.0) and a sulfonylurea receptor (SUR) subunit: Kir6.2 and SUR2A in cardiac myocytes, Kir6.2 and SUR1 in pancreatic β-cells. Sulfonylureas and glinides stimulate insulin secretion via blockade of the pancreatic β-cell K_ATP channel. Clinical studies about cardiotoxic effects of sulfonylureas are contradictory. Sulfonylureas and glinides differ in their selectivity for pancreatic over cardiovascular K_ATP channels, being either selective (tolbutamide, glibenclamide) or non-selective (repaglinide). The possibility exists that non-selective K_ATP channel inhibitors might have cardiovascular side effects. Blockers of the pore-forming Kir6.2 subunit are insulin secretagogues and might have cardioprotective or cardiotoxic effects during cardiac ischaemia.
Effects of lomefloxacin and norfloxacin on pancreatic β-cell ATP-sensitive K+ channels
2003, Life Sciences
In patients administered lomefloxacin alterations in blood glucose concentrations have been observed in some cases and lomefloxacin has previously been shown to augment insulin release from rat pancreatic islets at micromolar concentrations. The aim of the present study was to compare the effects of two structurally related fluoroquinolones, lomefloxacin and norfloxacin, on ATP-sensitive K⁺ (K_ATP) currents from the clonal insulinoma cell line RINm5F using the whole-cell configuration of the patch-clamp technique. The application of lomefloxacin concentration-dependently blocked K_ATP currents from RINm5F cells with a half-maximally inhibitory concentration of 81 μM, whereas the application of norfloxacin (at concentrations up to 300 μM) had only minor effects on K_ATP currents. Block of pancreatic β-cell K_ATP currents could be mediated by interaction of lomefloxacin either with the regulatory subunit (SUR1) or with the pore-forming subunit (Kir6.2). We favour the latter hypothesis, since some fluoroquinolones have recently been shown to block the pore-forming subunit of the cardiac rapid delayed rectifier K⁺ current I_Kr (which is encoded by HERG (human ether-a-go-go-related gene)). Thus, as demonstrated for cardiac HERG channels in previous studies and for pancreatic β-cell K_ATP channels in the present study, fluoroquinolones differ markedly in their potencies to inhibit K⁺ channel activity.
Ionic Mechanisms of Disopyramide Prolonging Action Potential Duration in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1
2020, Frontiers in Pharmacology
ATP-sensitive K+ channels
2012, Ion Channels: From Structure to Function
Report and recommendations of the workshop of the European centre for the validation of alternative methods for drug-induced cardiotoxicity
2009, Cardiovascular Toxicology
Vascular effects of antiarrhythmic drugs and the roles of K+ channels
2004, Current Medicinal Chemistry: Cardiovascular and Hematological Agents

View all citing articles on Scopus

View full text

Article preview

Life Sciences

Abstract

References (20)

Eur. J. Pharmacol.

Biochem. Biophys. Res. Commun.

Am. J. Cardiol.

Cardiovasc. Res.

Cardiovasc. Res.

J. Pharmacol. Exp. Ther.

Am. J. Physiol.

Physiol. Rev.

Nature

Pflügers Arch.

Cited by (8)

Human ether-a-go-go-related (HERG) gene and ATP-sensitive potassium channels as targets for adverse drug effects

Effects of lomefloxacin and norfloxacin on pancreatic β-cell ATP-sensitive K<sup>+</sup> channels

Ionic Mechanisms of Disopyramide Prolonging Action Potential Duration in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

ATP-sensitive K<sup>+</sup> channels

Report and recommendations of the workshop of the European centre for the validation of alternative methods for drug-induced cardiotoxicity

Vascular effects of antiarrhythmic drugs and the roles of K<sup>+</sup> channels

Pharmacology letter accelerated communicationDisopyramide block of KATP channels is mediated by the pore-forming subunit

Abstract

Eur. J. Pharmacol.

Biochem. Biophys. Res. Commun.

Am. J. Cardiol.

Cardiovasc. Res.

Cardiovasc. Res.

J. Pharmacol. Exp. Ther.

Am. J. Physiol.

Physiol. Rev.

Nature

Pflügers Arch.

Pharmacology letter accelerated communication
Disopyramide block of K_ATP channels is mediated by the pore-forming subunit