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Human ether-a-go-go-related (HERG) gene and ATP-sensitive potassium channels as targets for adverse drug effects.
Pharmacol Ther. 2006 Oct; 112(1):12-37.P&T

Abstract

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 (IKr), 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+ (KATP) 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). KATP 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 beta-cells. Sulfonylureas and glinides stimulate insulin secretion via blockade of the pancreatic beta-cell KATP channel. Clinical studies about cardiotoxic effects of sulfonylureas are contradictory. Sulfonylureas and glinides differ in their selectivity for pancreatic over cardiovascular KATP channels, being either selective (tolbutamide, glibenclamide) or non-selective (repaglinide). The possibility exists that non-selective KATP 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.

Authors+Show Affiliations

Federal Institute for Drugs and Medical Devices, Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany. zuenkler@bfarm.de

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

16647758

Citation

Zünkler, Bernd J.. "Human Ether-a-go-go-related (HERG) Gene and ATP-sensitive Potassium Channels as Targets for Adverse Drug Effects." Pharmacology & Therapeutics, vol. 112, no. 1, 2006, pp. 12-37.
Zünkler BJ. Human ether-a-go-go-related (HERG) gene and ATP-sensitive potassium channels as targets for adverse drug effects. Pharmacol Ther. 2006;112(1):12-37.
Zünkler, B. J. (2006). Human ether-a-go-go-related (HERG) gene and ATP-sensitive potassium channels as targets for adverse drug effects. Pharmacology & Therapeutics, 112(1), 12-37.
Zünkler BJ. Human Ether-a-go-go-related (HERG) Gene and ATP-sensitive Potassium Channels as Targets for Adverse Drug Effects. Pharmacol Ther. 2006;112(1):12-37. PubMed PMID: 16647758.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Human ether-a-go-go-related (HERG) gene and ATP-sensitive potassium channels as targets for adverse drug effects. A1 - Zünkler,Bernd J, Y1 - 2006/05/02/ PY - 2006/03/06/received PY - 2006/03/07/accepted PY - 2006/5/2/pubmed PY - 2007/1/11/medline PY - 2006/5/2/entrez SP - 12 EP - 37 JF - Pharmacology & therapeutics JO - Pharmacol. Ther. VL - 112 IS - 1 N2 - 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 (IKr), 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+ (KATP) 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). KATP 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 beta-cells. Sulfonylureas and glinides stimulate insulin secretion via blockade of the pancreatic beta-cell KATP channel. Clinical studies about cardiotoxic effects of sulfonylureas are contradictory. Sulfonylureas and glinides differ in their selectivity for pancreatic over cardiovascular KATP channels, being either selective (tolbutamide, glibenclamide) or non-selective (repaglinide). The possibility exists that non-selective KATP 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. SN - 0163-7258 UR - https://www.unboundmedicine.com/medline/citation/16647758/Human_ether_a_go_go_related__HERG__gene_and_ATP_sensitive_potassium_channels_as_targets_for_adverse_drug_effects_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0163-7258(06)00031-3 DB - PRIME DP - Unbound Medicine ER -