Abstract
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+/Ca2+-exchanger (NCX) The driving force of the NCX (ΔGncx) determines the activity of NCX. The aim of this study was to describe the relation between ΔGncx and calcium homeostasis during metabolic inhibition. Methods: In left ventricular rabbit myocytes, during metabolic inhibition (2 mmol/L sodium cyanide), sodium ([Na+]i), calcium ([Ca2+;]i), and action potentials were determined with SBFI, indo-1, and the patch clamp technique. Changes of ΔGncx 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 ΔGncx 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 ΔGncx caused by shortening of the action potential. The increase of ΔGncx contributed to decrease of diastolic calcium, calcium transient amplitude, SR calcium content, and contractility. The increase of diastolic calcium started after ΔGncx became lower than under aerobic conditions.
Highlights
The sarcolemmal Na+/Ca2+-exchanger (NCX) is a passive ion transport mechanism, which directly couples transmembrane movements of Ca2+ to reciprocal movements of Na+ with a stoichiometric ratio of three sodium per calcium (Reeves and Hale, 1984)
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%
Metabolic inhibition caused an early increase of ∆Gncx caused by shortening of the action potential.The increase of ∆Gncx contributed to decrease of diastolic calcium, calcium transient amplitude, SR calcium content, and contractility
Summary
Metabolic inhibition causes a decline in mechanical performance and, if prolonged, myocardial contracture and cell death. Methods: In left ventricular rabbit myocytes, during metabolic inhibition (2 mmol/L sodium cyanide), sodium ([Na+]i), calcium ([Ca2+]i), and action potentials were determined with SBFI, indo, and the patch clamp technique. 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 14 min action potential and calcium transients disappeared due to unexcitability of the myocytes. This resulted in an increased of the time average of ∆Gncx 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
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