Endothelin and cardiac arrhythmias: do endothelin antagonists have a therapeutic potential as antiarrhythmic drugs?
Endothelin-1 (ET-1), the predominant isoform of the ET peptide family and a potent vasoconstrictor, has been shown to aggravate ischemia-induced ventricular arrhythmias. However, there is also evidence that ET-1 may have a direct arrhythmogenic action that is not solely attributable to myocardial ischemia. Proposed mechanisms for the arrhythmogenic effects of ET-1 are prolongation or increased dispersion of monophasic action potential duration, QT prolongation, development of early afterdepolarizations, acidosis, and augmentation of cellular injury. As for an ionic basis for the observed electrophysiologic effects, ET-induced Ca(2+) release from intracellular stores, generation of inositol triphosphate, inhibition of delayed rectifier K(+) current, and stimulation of the Na(+)/H(+) exchanger may be involved. Recently, some studies have shown that ET receptor antagonists, which promise to be powerful tools in cardiovascular medicine, may also demonstrate antiarrhythmic properties. This review describes the current state of knowledge on the interactions between the ET system and cardiac arrhythmias, and discusses the therapeutic potential of ET antagonists as antiarrhythmic drugs.
Duru
F
F
Division of Cardiology, University Hospital of Zurich and Cardiovascular Research Laboratory, Institute of Physiology, University of Zurich, Zurich, Switzerland. firat.duru@dim.usz.ch
Barton
M
M
Lüscher
T F
TF
Candinas
R
R
D000200:Action Potentials; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000378:metabolism*; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D008955:Models, Cardiovascular; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007473:Ion Channels; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin