Therapeutic potential of modulating potassium currents in the diseased myocardium.
Myocardial disease states are characterized by multiple electrophysiologic abnormalities, including alterations in potassium channel activities. During acute myocardial ischemia, activation of ATP-regulated K+ current (IK(ATP)) results in shortening of action potential duration and elevation of extracellular K+ concentration. In hypertrophied myocardium, increases in inward rectifier K+ current (IK1) and decreases in delayed rectifier K+ current (IK) are observed. Alterations in K+ channel activity in myocardial disease states suggest the potential to therapeutically modify cardiac rhythm and function with K+ channel modulators. Class III anti-arrhythmic agents, which prolong myocardial refractoriness predominantly via a blockade of IK, have demonstrated efficacy in suppressing reentrant atrial and ventricular arrhythmias in animal models as well as promising efficacy in initial clinical studies. Potassium channel openers (PCOs), which activate cardiac IK(ATP), have demonstrated both antiarrhythmic and proarrhythmic activities in various experimental settings, and also are being investigated as potential cardioprotective agents. Sulfonylureas, which block cardiac IK(ATP), also have been investigated as potential antiarrhythmic agents with equivocal results, and have displayed a propensity to exacerbate ischemic myocardial dysfunction in experimental studies. A more comprehensive understanding of K+ channel activity in various myocardial disease states, including concomitant disorders such as myocardial ischemia and hypertrophy, will facilitate the development of more useful potassium channel modulators, as well as a clearer recognition of the undesirable effects of such agents.
Lynch
J J
JJ
Department of Pharmacology, Merck, Sharp and Dohme Research Laboratories, West Point, Pennsylvania 19486.
Sanguinetti
M C
MC
Kimura
S
S
Bassett
A L
AL
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D006332:Cardiomegaly / Q000188:drug therapy / Q000503:physiopathology; D003327:Coronary Disease / Q000188:drug therapy / Q000503:physiopathology; D006331:Heart Diseases / Q000188:drug therapy*; D006801:Humans; D015221:Potassium Channels / Q000187:drug effects*; D013453:Sulfonylurea Compounds / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D015221:Potassium Channels; D013453:Sulfonylurea Compounds