Blockers of the ATP-sensitive potassium channel SUR2A/Kir6.2: a new approach to prevent sudden cardiac death.
The cardiac ATP sensitive potassium channel (K(ATP) channel) SUR2A/Kir6.2 is an emerging target for antiarrhythmic intervention. This channel accounts for known electrophysiological derangements soon after the onset of myocardial ischemia. Consequently, blockers of this channel have the potential to prevent ischemic malignant arrhythmias and sudden cardiac death in humans. Since cardiac K(ATP) channels are closed at physiological intracellular ATP concentrations (ATP(i)) and open only when ATP(i) falls below a critical value, these agents do not affect the normal cardiac action potential and should be devoid of proarrhythmic side effects. Due to the existence of isoforms of this channel, mainly in vascular smooth muscle cells, pancreatic beta-cells and cardiac mitochondria, only specific blockers of SUR2A/Kir6.2 will offer a reasonable option for the treatment of cardiovascular patients at risk of sudden cardiac death. Presently known K(ATP) blockers are derived from diverse classes of compounds with antidiabetic sulfonylureas being their most prominent members. Retrospective evaluations of clinical studies with the sulfonylurea glibenclamide in diabetics revealed antifibrillatory activity to be an important additional effect of this class of compounds. However, for the safe treatment of arrhythmias nearly all presently known blockers lack sufficient selectivity, either within the target family or with respect to other ion channels modulating the cardiac action potential. The present article illustrates the new principle in terms of molecular biology and electrophysiology and summarizes all presently known K(ATP) blockers. As a highlight, first strategies to come to selective SUR2A/Kir6.2 blockers, such as HMR 1883, are reviewed.
Englert
Heinrich C
HC
Aventis Pharma Deutschland GmbH, DI&A, Medicinal Chemistry, 65926 Frankfurt/Main, Germany. heinrich.englert@aventis.com
Heitsch
Holger
H
Gerlach
Uwe
U
Knieps
Stephanie
S
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000889:Anti-Arrhythmia Agents / Q000737:chemistry* / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000188:drug therapy; D016757:Death, Sudden, Cardiac / Q000517:prevention & control*; D004594:Electrophysiology; D005905:Glyburide / Q000737:chemistry / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013453:Sulfonylurea Compounds / Q000737:chemistry / Q000494:pharmacology; D064233:Sulfonylurea Receptors
C577510:ABCC9 protein, human; D018528:ATP-Binding Cassette Transporters; D000889:Anti-Arrhythmia Agents; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; D000255:Adenosine Triphosphate; D005905:Glyburide