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(Circulation. 2002;106:613.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Long-Term Endothelin A Receptor Blockade Inhibits Electrical Remodeling in Cardiomyopathic Hamsters

Yasunori Matsumoto, MD, PhD; Hajime Aihara, MS; Rikako Yamauchi-Kohno, PhD; Yoshie Reien, BS; Takehiko Ogura, MD; Hideo Yabana, PhD; Yoshiaki Masuda, MD, PhD; Toshiaki Sato, MD, PhD; Issei Komuro, MD, PhD; Haruaki Nakaya, MD, PhD

From the Departments of Pharmacology (Y. Matsumoto, Y.R., T.O., T.S., H.N.) and Cardiovascular Science and Medicine (Y. Matsumoto, Y. Masuda, I.K.), Chiba University Graduate School of Medicine, Chiba, Japan; and Discovery Research Laboratory (H.A., R.Y.-K., H.Y.), Tanabe Seiyaku Co Ltd, Saitama, Japan.

Correspondence to Dr H. Nakaya, Department of Pharmacology, Chiba University Graduate School of Medicine, Inohana 1-8-1, Chuo-ku, Chiba 260-8670, Japan. E-mail nakaya@ med.m.chiba-u.ac.jp

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 ET_A 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 F1ß hamsters and cardiomyopathic BIO 14.6 hamsters untreated and chronically treated with TA-0201, an ET_A 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 (I_Ca,L), the transient outward current (I_to), the delayed rectifier K⁺ current (I_K), and the inward rectifier K⁺ current (I_K1) were decreased compared with those of F1ß hamsters. Long-term treatment with the ET_A receptor antagonist significantly attenuated action potential duration prolongation and reduction of I_to, I_K, and I_Ca,L in BIO 14.6 ventricular cells. Long-term ET_A receptor blockade prevented the QT prolongation and ventricular arrhythmias and improved the survival rate in the cardiomyopathic hamsters.

Conclusions— Long-term treatment with an ET_A 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. ET_A receptor blockade may provide a new strategy for the prevention of ventricular arrhythmias associated with heart failure.

Key Words: endothelin • ion channels • cardiomyopathy • electrophysiology

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