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 ventr icular arrhythmias. However, there is also evidence that ET-1 may have a di rect arrhythmogenic action that is not solely attributable to myocardial is chemia. Proposed mechanisms for the arrhythmogenic effects of ET-1 are prol ongation or increased dispersion of monophasic action potential duration, Q T prolongation, development of early afterdepolarizations, acidosis, and au gmentation of cellular injury. As for an ionic basis for the observed elect rophysiologic effects, ET-induced Ca2+ release from intracellular stores, g eneration of inositol triphosphate, inhibition of delayed rectifier K+ curr ent, and stimulation of the Na+/H+ exchanger may be involved. Recently, som e studies have shown that ET receptor antagonists, which promise to be powe rful tools in cardiovascular medicine, may also demonstrate antiarrhythmic properties. This review describes the current state of knowledge on the int eractions between the ET system and cardiac arrhythmias, and discusses the therapeutic potential of ET antagonists as antiarrhythmic drugs. (C) 2001 E lsevier Science E.V. All rights reserved.