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Long-term endothelin a receptor blockade inhibits electrical remodeling in cardiomyopathic hamsters
Yasunori Matsumoto1, Hajime Aihara, Rikako Yamauchi-Kohno
1Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan.
Insights
Long-term ET(A) receptor blockade in cardiomyopathic hamsters prevented ventricular arrhythmias and improved survival. This treatment inhibited electrical remodeling, offering a new strategy for heart failure patients.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Electrophysiology
Background:
- The endothelin (ET) system is implicated in heart failure.
- Congestive heart failure is linked to ventricular arrhythmias due to electrical remodeling.
- Electrical remodeling involves changes in ionic current density and action potential duration.
Purpose of the Study:
- To investigate the effects of long-term ET(A) receptor blockade on electrophysiological properties.
- To assess the impact on surface ECG and survival in BIO 14.6 cardiomyopathic hamsters.
Main Methods:
- Recorded membrane currents and action potentials from ventricular cells of normal and cardiomyopathic hamsters.
- Compared untreated cardiomyopathic hamsters with those chronically treated with an ET(A) receptor antagonist (TA-0201).
Main Results:
- Untreated cardiomyopathic hamsters showed prolonged action potential duration and reduced ionic currents (I(Ca,L), I(to), I(K), I(K1)).
- ET(A) receptor antagonist treatment attenuated action potential prolongation and preserved ionic current densities.
- Long-term blockade prevented QT prolongation, ventricular arrhythmias, and improved survival rates.
Conclusions:
- Long-term ET(A) antagonist treatment inhibits electrical remodeling in cardiomyopathic hearts.
- This blockade suppresses ventricular arrhythmias by normalizing K+ and Ca2+ currents and action potential duration.
- ET(A) receptor blockade presents a potential therapeutic strategy for arrhythmias in heart failure.
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.
