title: Sarcolemmal KATP channel modulators and cardiac arrhythmias.
abstract: Cardiac atrial and ventricular arrhythmias are major causes of mortality and morbidity. Ischemic heart disease is the most common cause underlying 1) the development of ventricular fibrillation that results in sudden cardiac death and 2) atrial fibrillation that can lead to heart failure and stroke. Current pharmacological agents for the treatment of ventricular and atrial arrhythmias exhibit limited effectiveness and many of these agents can cause serious adverse effects - including the provocation of lethal ventricular arrhythmias. Sarcolemmal ATP-sensitive potassium channels (sarcK(ATP)) couple cellular metabolism to membrane excitability in a wide range of tissues. In the heart, sarcK(ATP) are activated during metabolic stress including myocardial ischemia, and both the opening of sarcK(ATP) and mitochondrial K(ATP) channels protect the ischemic myocardium via distinct mechanisms. Myocardial ischemia leads to a series of events that promote the generation of arrhythmia substrate eventually resulting in the development of life-threatening arrhythmias. In this review, the possible mechanisms of the anti- and proarrhythmic effects of sarcK(ATP) modulation as well as the influence of pharmacological K(ATP) modulators are discussed. It is concluded that in spite of the significant advances made in this field, the possible cardiovascular therapeutic utility of current sarcK(ATP) channel modulators is still hampered by the lack of chamber-specific selectivity. However, recent insights into the chamber-specific differences in the molecular composition of sarcKATP in addition to already existing cardioselective sarcK(ATP) channel modulators with sarcK(ATP) isoform selectivity holds the promise for the future development of pharmacological strategies specific for a variety of atrial and ventricular arrhythmias.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Szeged, Dóm tér 12., H-6720 Szeged, Hungary. ibaczko@phcol.szote.u-szeged.hu
authors.forename: I
authors.initials: I
authors.lastname: Baczkó
authors.forename: Z
authors.initials: Z
authors.lastname: Husti
authors.forename: V
authors.initials: V
authors.lastname: Lang
authors.forename: I
authors.initials: I
authors.lastname: Leprán
authors.forename: P E
authors.initials: PE
authors.lastname: Light
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000627:therapeutic use; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism*
chemical_list: D000889:Anti-Arrhythmia Agents; D054086:KATP Channels; D026902:Potassium Channel Blockers; D020033:Protein Isoforms