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Chronic endothelin-1 blockade preserves myocardial contractility in dilated cardiomyopathy
A S Pandey1, D J Stewart, P Cernacek
1Center for Cardiovascular Research, Toronto Hospital, Ontario, Canada.
Insights
Endothelin-1 (ET-1) normally supports heart function, but its chronic elevation in heart failure impairs performance. Blocking ET-1 in healthy hearts reduced contractility, while preserving it in failing hearts.
Area of Science:
- Cardiology
- Pharmacology
- Physiology
Background:
- Endothelin-1 (ET-1) exhibits positive inotropic effects on isolated cardiac muscle.
- Elevated ET-1 levels are a hallmark of congestive heart failure (CHF).
Purpose of the Study:
- To investigate the impact of chronic ET-1 blockade on cardiac contractility and relaxation in healthy and failing murine hearts.
- To elucidate the role of ET-1 in basal cardiac function versus its role in pathological states like myocarditis/cardiomyopathy.
Main Methods:
- Utilized a mixed ETA/ETB receptor blocker, SB217242, administered orally for chronic treatment.
- Assessed cardiac contractility and lusitropy in intact healthy and myocarditic/cardiomyopathic murine hearts.
Main Results:
- Chronic ET-1 blockade depressed contractility and lusitropy in normal hearts.
- In contrast, ET-1 blockade preserved and enhanced contractility and lusitropy in myocarditic/cardiomyopathic hearts with elevated ET-1 levels.
Conclusions:
- ET-1 is crucial for maintaining basal contractility and relaxation in healthy hearts.
- Chronic elevation of ET-1 in CHF contributes to impaired cardiac systolic and diastolic performance.
Abstract:
Endothelin-1 (ET-1) is known to have positive inotropic effects in isolated cardiac muscle strips. ET-1 levels are elevated in congestive heart failure (CHF). We investigated the effects of ET-1 on contractility and cardiac relaxation (lusitropy) of the intact healthy murine heart and myocarditic/cardiomyopathic heart by chronic oral treatment with a mixed ETA/ETB blocker SB217242. Chronic ET-1 blockade of normal hearts resulted in depression of contractility and lusitropy of the normal heart but preservation and enhancement of contractility and lusitropy in myocarditic animals, in which ET-1 cardiac content is elevated. This suggests that ET-1 is important in the basal contractility and relaxation of the normal heart but that its chronic elevation in CHF causes impairment of cardiac systolic and diastolic performance.