Structural determinants of potassium channel blockade and drug-induced arrhythmias.
Cardiac K+ channels play an important role in the regulation of the shape and duration of the action potential. They have been recognized as targets for the actions of neurotransmitters, hormones, and anti-arrhythmic drugs that prolong the action potential duration (APD) and increase refractoriness. However, pharmacological therapy, often for the purpose of treating syndromes unrelated to cardiac disease, can also increase the vul- nerability of some patients to life-threatening rhythm disturbances. This may be due to an underlying propensity stemming from inherited mutations or polymorphisms, or structural abnormalities that provide a substrate allowing for the initiation of arrhythmic triggers. A number of pharmacological agents that have proved useful in the treatment of allergic reactions, gastrointestinal disorders, and psychotic disorders, among others, have been shown to reduce repolarizing K+ currents and prolong the Q-T interval on the electrocardiogram. Understanding the structural determinants of K+ channel blockade might provide new insights into the mechanism and rate-dependent effects of drugs on cellular physiology. Drug-induced disruption of cellular repolarization underlies electrocardiographic abnormalities that are diagnostic indicators of arrhythmia susceptibility.
Wehrens
X H T
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Center for Molecular Cardiology, Dept. of Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University, 630 West 168th Street, P&S 9-401, New York, NY 10032, USA. xw80@columbia.edu
D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D051668:Delayed Rectifier Potassium Channels / Q000502:physiology; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006321:Heart / Q000502:physiology; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000502:physiology; D051657:KCNQ1 Potassium Channel / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology; D008133:Long QT Syndrome / Q000235:genetics; D026902:Potassium Channel Blockers / Q000009:adverse effects / Q000494:pharmacology*; D015221:Potassium Channels / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology; D013329:Structure-Activity Relationship
D051668:Delayed Rectifier Potassium Channels; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D051657:KCNQ1 Potassium Channel; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated