Long-term endothelin a receptor blockade inhibits electrical remodeling in cardiomyopathic hamsters.

Abstract

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 F1beta 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 F1beta 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.

• Authors: Yasunori Matsumoto, Hajime Aihara, Rikako Yamauchi-Kohno, Yoshie Reien, Takehiko Ogura, Hideo Yabana, Yoshiaki Masuda, Toshiaki Sato, Issei Komuro, Haruaki Nakaya
• Journal: Circulation (Circulation) Vol. 106 Issue 5 Pg. 613-9 (Jul 30 2002) ISSN: 1524-4539 [Electronic] United States
• PMID: 12147545 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channels, L-Type
• Endothelin Receptor Antagonists
• Potassium Channels, Inwardly Rectifying
• Pyrimidines
• Receptor, Endothelin A
• Sulfonamides
• T 0201
• Calcium

Topics

• Action Potentials (drug effects, physiology)
• Animals
• Calcium (metabolism)
• Calcium Channels, L-Type (metabolism)
• Cardiomyopathies (drug therapy, physiopathology)
• Chronic Disease
• Cricetinae
• Disease Models, Animal
• Electrocardiography (drug effects)
• Electrophysiologic Techniques, Cardiac
• Endothelin Receptor Antagonists
• Heart Conduction System (drug effects, physiopathology)
• Heart Ventricles (cytology, drug effects, physiopathology)
• Male
• Myocardium (cytology)
• Patch-Clamp Techniques
• Potassium Channels, Inwardly Rectifying (metabolism)
• Pyrimidines (therapeutic use)
• Receptor, Endothelin A
• Sulfonamides (therapeutic use)
• Survival Rate
• Time