Long-Term Endothelin A Receptor Blockade Inhibits Electrical Remodeling in Cardiomyopathic Hamsters
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Background— The endothelin (ET) system is activated in failing hearts. Congestive heart failure frequently is associated with ventricular arrhythmias, which may result from electrical remodeling such as changes of ionic current density and heterogeneous action potential prolongation. We examined the effects of long-term ETA receptor blockade on the electrophysiological properties of ventricular cells, the surface ECG, and the survival in BIO 14.6 cardiomyopathic hamsters.
Methods and Results— Membrane currents and action potentials were recorded from left ventricular cells isolated from normal F1β hamsters and cardiomyopathic BIO 14.6 hamsters untreated and chronically treated with TA-0201, an ETA receptor antagonist. In ventricular cells of untreated BIO 14.6 hamsters, the action potential duration was prolonged and the densities of the L-type Ca2+ current (ICa,L), the transient outward current (Ito), the delayed rectifier K+ current (IK), and the inward rectifier K+ current (IK1) were decreased compared with those of F1β hamsters. Long-term treatment with the ETA receptor antagonist significantly attenuated action potential duration prolongation and reduction of Ito, IK, and ICa,L in BIO 14.6 ventricular cells. Long-term ETA receptor blockade prevented the QT prolongation and ventricular arrhythmias and improved the survival rate in the cardiomyopathic hamsters.
Conclusions— Long-term treatment with an ETA antagonist inhibits electrical remodeling such as downregulation of K+ and Ca2+ currents, action potential prolongation, and the increased QT interval and thereby suppresses ventricular arrhythmias in cardiomyopathic hearts. ETA receptor blockade may provide a new strategy for the prevention of ventricular arrhythmias associated with heart failure.
Received April 8, 2002; revision received May 7, 2002; accepted May 7, 2002.