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The Driving Force of the Na/Ca-Exchanger during Metabolic Inhibition
Antonius Baartscheer1, Cees A Schumacher, Ruben Coronel
1Experimental Cardiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam Amsterdam, Netherlands.
Objective:
Metabolic inhibition causes a decline in mechanical performance and, if prolonged, myocardial contracture and cell death. The decline in mechanical performance is mainly due to altered intracellular calcium handling, which is under control of the Na(+)/Ca(2+)-exchanger (NCX) The driving force of the NCX (ΔG(ncx)) determines the activity of NCX. The aim of this study was to describe the relation between ΔG(ncx) and calcium homeostasis during metabolic inhibition.
Methods:
In left ventricular rabbit myocytes, during metabolic inhibition (2 mmol/L sodium cyanide), sodium ([Na(+)](i)), calcium ([Ca(2+);](i)), and action potentials were determined with SBFI, indo-1, and the patch clamp technique. Changes of ΔG(ncx) were calculated.
Results:
During metabolic inhibition: The first 8 min [Na(+)](i) remained constant, systolic calcium decreased from 532 ± 28 to 82 ± 13 nM, diastolic calcium decreased from 121 ± 12 to 36 ± 10 nM and the sarcoplasmic reticulum (SR) calcium content was depleted for 85 ± 3%. After 8 min [Na(+);](i) and diastolic calcium started to increase to 30 ± 1.3 mmol/L and 500 ± 31 nM after 30 min respectively. The action potential duration shortened biphasically. In the first 5 min it shortened from 225 ± 12 to 153 ± 11 ms and remained almost constant until it shortened again after 10 min. After 14 min action potential and calcium transients disappeared due to unexcitability of the myocytes. This resulted in an increased of the time average of ΔG(ncx) from 6.2 ± 0.2 to 7.7 ± 0.3 kJ/mol during the first 3 min, where after it decreased and became negative after about 15 min.
Conclusion:
Metabolic inhibition caused an early increase of ΔG(ncx) caused by shortening of the action potential. The increase of ΔG(ncx) contributed to decrease of diastolic calcium, calcium transient amplitude, SR calcium content, and contractility. The increase of diastolic calcium started after ΔG(ncx) became lower than under aerobic conditions.
Insights
Metabolic inhibition initially increases the driving force of the Na(+)/Ca(2+)-exchanger (NCX), leading to reduced intracellular calcium and impaired heart cell function. Later, decreased NCX driving force contributes to calcium overload and loss of excitability.
Area of Science:
- Cardiology
- Cell Physiology
- Biophysics
Background:
- Metabolic inhibition impairs cardiac mechanical performance by altering intracellular calcium handling.
- The Na(+)/Ca(2+) exchanger (NCX) plays a critical role in regulating intracellular calcium levels.
- The driving force of the NCX (ΔG(ncx)) dictates its activity.
Purpose of the Study:
- To investigate the relationship between the NCX driving force (ΔG(ncx)) and calcium homeostasis during metabolic inhibition in cardiac myocytes.
Main Methods:
- Rabbit ventricular myocytes were subjected to metabolic inhibition using sodium cyanide.
- Intracellular sodium ([Na(+)](i)) and calcium ([Ca(2+)](i)) were measured using SBFI and indo-1.
- Action potentials were recorded using the patch clamp technique.
- Changes in ΔG(ncx) were calculated based on measured ionic concentrations and potentials.
Main Results:
- Metabolic inhibition initially decreased systolic and diastolic calcium and sarcoplasmic reticulum (SR) calcium content.
- Intracellular sodium and diastolic calcium levels increased after 8 minutes.
- Action potential duration shortened biphasically, leading to unexcitability and loss of calcium transients after 14 minutes.
- ΔG(ncx) initially increased, then decreased, becoming negative after approximately 15 minutes.
Conclusions:
- Early increase in ΔG(ncx) during metabolic inhibition, driven by action potential shortening, contributes to reduced calcium transient amplitude and contractility.
- The subsequent rise in diastolic calcium occurs when ΔG(ncx) falls below aerobic levels.
- These findings highlight the dynamic interplay between NCX function and calcium handling during metabolic stress in cardiomyocytes.
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