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Peroxynitrite impairs cardiac contractile function by decreasing cardiac efficiency
R Schulz1, K L Dodge, G D Lopaschuk
1Department of Pediatrics, University of Alberta, Edmonton, Canada. richard.schulz@ualberta.ca
Abstract:
Peroxynitrite (ONOO-) inhibits energy metabolism in isolated cells and mitochondria and may be involved in the depression of cardiac mechanical function during pathophysiological states. We determined the actions of ONOO- on cardiac function and energy metabolism in isolated working rat hearts and compared them with the NO donor S-nitroso-DL-acetylpenicillamine (SNAP). After a 15-min baseline aerobic perfusion, ONOO- (4 or 40 microM), SNAP (40 microM), or their vehicles were infused over a 60-min period. ONOO- or SNAP (40 microM each) caused a rapid and sustained rise in coronary flow. Infusion of 40 microM (but not 4 microM) ONOO- caused a marked depression in cardiac work with a delayed onset but no change in O2 consumption, resulting in a marked loss of cardiac efficiency. Cardiac work, O2 consumption, and cardiac efficiency remained constant in vehicle- and SNAP-treated hearts. ONOO- (40 microM) enhanced glycolysis and glucose oxidation but did not change pyruvate oxidation compared with its vehicle control, whereas SNAP was without effect. ONOO(-)-mediated depression in cardiac efficiency may be due to reduced coupling between ATP production and mechanical work.
Insights
High concentrations of peroxynitrite (ONOO-) impair heart function and efficiency by disrupting energy metabolism, unlike the NO donor SNAP. This suggests ONOO- negatively impacts cardiac performance during disease.
Area of Science:
- Biochemistry
- Cardiovascular Physiology
- Cellular Metabolism
Background:
- Peroxynitrite (ONOO-) is implicated in cellular dysfunction and cardiac mechanical depression during pathophysiological conditions.
- Understanding the specific effects of ONOO- on cardiac energy metabolism and function is crucial for elucidating its role in heart disease.
Purpose of the Study:
- To investigate the impact of peroxynitrite (ONOO-) on cardiac function and energy metabolism in isolated working rat hearts.
- To compare the effects of ONOO- with those of a nitric oxide (NO) donor, S-nitroso-DL-acetylpenicillamine (SNAP).
Main Methods:
- Isolated working rat hearts were perfused under aerobic conditions.
- Hearts were treated with either ONOO- (4 or 40 microM), SNAP (40 microM), or vehicle controls over a 60-minute infusion period.
- Cardiac function (work), oxygen consumption, coronary flow, and substrate oxidation (glucose, pyruvate) were measured.
Main Results:
- High-dose ONOO- (40 microM) significantly reduced cardiac work and efficiency with a delayed onset, without altering oxygen consumption.
- ONOO- enhanced glycolysis and glucose oxidation but did not affect pyruvate oxidation.
- SNAP and vehicle treatments did not alter cardiac function, oxygen consumption, or metabolic parameters.
Conclusions:
- Peroxynitrite (ONOO-) depresses cardiac mechanical efficiency, potentially by uncoupling ATP production from mechanical work.
- The observed effects of ONOO- on cardiac efficiency are distinct from those of the NO donor SNAP.
- ONOO- appears to interfere with specific pathways of cardiac energy metabolism, contributing to functional decline.