Energetic modulation of cardiac inotropism and sarcoplasmic reticular Ca2+ uptake

Robert T. Mallet, Rolf Bünger

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Myocardial contractile performance is a function of sarcoplasmic reticular Ca2+ uptake and release, Ca2+ handling is ATP-dependent and can account for up to 40% of total myocardial energy expenditure. We tested the hypothesis that the thermodynamics of the cytosolic adenylate system can modulate sarcoplasmic reticular Ca2+ handling and hence function in intact heart. Cellular energy level was experimentally manipulated by perfusing isolated working guinea-pig hearts with substrate-free medium or media fortified with lactate and/or pyruvate as the main energy substrate. Left ventricular contractile function was judged by stroke work and intraventricular dP dt. Cytosolic energy level was indexed by measured creatine kinase reactants. Relative to 5 mM lactate, 5 mM pyruvate increased left ventricular stroke work, dP dtmax, and dP dtmin, while lowering left ventricular end-diastolic pressure at physiological left atrial and aortic pressures. Pyruvate also doubled cytosolic phosphorylation potentials and increased [ATP] [ADP] ratio; this energetic enhancement distinguishes pyruvate from inotropic stimulation by catecholamines, which are known to decrease cytosolic energy level in perfused heart. Sarcoplasmic reticular Ca2+ handling was assessed in hearts prelabeled with 45Ca, subjected to 45Ca washout in the presence of different cytosolic energy levels, then stimulated with 10 mM caffeine to release residual sarcoplasmic reticular 45Ca. When ryanodine (1 μM) was applied to open Ca2+ channels and thereby released 45Ca from the sarcoplasmic reticulum during washout, caffeine-stimulated 45Ca release was decreased 96%, demonstrating that virtually the entire caffeine-sensitive 45Ca pool was located in the sarcoplasmic reticulum. In detailed comparisons of pyruvate-energized vs. substrate-free deenergized hearts, an inverse relationship between cytosolic energy level and caffeine-mobilized 45Ca pool size was observed. Thus, caffeine-induced 45Ca release was decreased 60% by pyruvate energization and increased 2.5-fold by substrate-free deenergization. Taken together, these results support the hypothesis that enhancement of myocardial inotropism by energy-yielding substrate is mediated by increased sarcoplasmic reticular Ca2+ loading/release. Thus we propose that the known control of sarcoplasmic reticular Ca2+ turnover by the protein kinase/phospholamban system can be modulated by cytosolic energy level.

Original languageEnglish
Pages (from-to)22-32
Number of pages11
JournalBBA - Molecular Cell Research
Volume1224
Issue number1
DOIs
StatePublished - 20 Oct 1994

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Myocardial Contraction
Pyruvic Acid
Caffeine
Sarcoplasmic Reticulum
Lactic Acid
Adenosine Triphosphate
Stroke
Ryanodine
Atrial Pressure
Creatine Kinase
Muscle Contraction
Left Ventricular Function
Thermodynamics
Adenosine Diphosphate
Protein Kinases
Energy Metabolism
Catecholamines
Arterial Pressure
Guinea Pigs
Phosphorylation

Keywords

  • ATPase, Ca-
  • Caffeine
  • Cytosolic phosphorylation potential
  • Pyruvate
  • Ryanodine
  • Sarcoplasmic reticulum
  • Ventricular myocardium

Cite this

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title = "Energetic modulation of cardiac inotropism and sarcoplasmic reticular Ca2+ uptake",
abstract = "Myocardial contractile performance is a function of sarcoplasmic reticular Ca2+ uptake and release, Ca2+ handling is ATP-dependent and can account for up to 40{\%} of total myocardial energy expenditure. We tested the hypothesis that the thermodynamics of the cytosolic adenylate system can modulate sarcoplasmic reticular Ca2+ handling and hence function in intact heart. Cellular energy level was experimentally manipulated by perfusing isolated working guinea-pig hearts with substrate-free medium or media fortified with lactate and/or pyruvate as the main energy substrate. Left ventricular contractile function was judged by stroke work and intraventricular dP dt. Cytosolic energy level was indexed by measured creatine kinase reactants. Relative to 5 mM lactate, 5 mM pyruvate increased left ventricular stroke work, dP dtmax, and dP dtmin, while lowering left ventricular end-diastolic pressure at physiological left atrial and aortic pressures. Pyruvate also doubled cytosolic phosphorylation potentials and increased [ATP] [ADP] ratio; this energetic enhancement distinguishes pyruvate from inotropic stimulation by catecholamines, which are known to decrease cytosolic energy level in perfused heart. Sarcoplasmic reticular Ca2+ handling was assessed in hearts prelabeled with 45Ca, subjected to 45Ca washout in the presence of different cytosolic energy levels, then stimulated with 10 mM caffeine to release residual sarcoplasmic reticular 45Ca. When ryanodine (1 μM) was applied to open Ca2+ channels and thereby released 45Ca from the sarcoplasmic reticulum during washout, caffeine-stimulated 45Ca release was decreased 96{\%}, demonstrating that virtually the entire caffeine-sensitive 45Ca pool was located in the sarcoplasmic reticulum. In detailed comparisons of pyruvate-energized vs. substrate-free deenergized hearts, an inverse relationship between cytosolic energy level and caffeine-mobilized 45Ca pool size was observed. Thus, caffeine-induced 45Ca release was decreased 60{\%} by pyruvate energization and increased 2.5-fold by substrate-free deenergization. Taken together, these results support the hypothesis that enhancement of myocardial inotropism by energy-yielding substrate is mediated by increased sarcoplasmic reticular Ca2+ loading/release. Thus we propose that the known control of sarcoplasmic reticular Ca2+ turnover by the protein kinase/phospholamban system can be modulated by cytosolic energy level.",
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Energetic modulation of cardiac inotropism and sarcoplasmic reticular Ca2+ uptake. / Mallet, Robert T.; Bünger, Rolf.

In: BBA - Molecular Cell Research, Vol. 1224, No. 1, 20.10.1994, p. 22-32.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Energetic modulation of cardiac inotropism and sarcoplasmic reticular Ca2+ uptake

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AU - Bünger, Rolf

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Y1 - 1994/10/20

N2 - Myocardial contractile performance is a function of sarcoplasmic reticular Ca2+ uptake and release, Ca2+ handling is ATP-dependent and can account for up to 40% of total myocardial energy expenditure. We tested the hypothesis that the thermodynamics of the cytosolic adenylate system can modulate sarcoplasmic reticular Ca2+ handling and hence function in intact heart. Cellular energy level was experimentally manipulated by perfusing isolated working guinea-pig hearts with substrate-free medium or media fortified with lactate and/or pyruvate as the main energy substrate. Left ventricular contractile function was judged by stroke work and intraventricular dP dt. Cytosolic energy level was indexed by measured creatine kinase reactants. Relative to 5 mM lactate, 5 mM pyruvate increased left ventricular stroke work, dP dtmax, and dP dtmin, while lowering left ventricular end-diastolic pressure at physiological left atrial and aortic pressures. Pyruvate also doubled cytosolic phosphorylation potentials and increased [ATP] [ADP] ratio; this energetic enhancement distinguishes pyruvate from inotropic stimulation by catecholamines, which are known to decrease cytosolic energy level in perfused heart. Sarcoplasmic reticular Ca2+ handling was assessed in hearts prelabeled with 45Ca, subjected to 45Ca washout in the presence of different cytosolic energy levels, then stimulated with 10 mM caffeine to release residual sarcoplasmic reticular 45Ca. When ryanodine (1 μM) was applied to open Ca2+ channels and thereby released 45Ca from the sarcoplasmic reticulum during washout, caffeine-stimulated 45Ca release was decreased 96%, demonstrating that virtually the entire caffeine-sensitive 45Ca pool was located in the sarcoplasmic reticulum. In detailed comparisons of pyruvate-energized vs. substrate-free deenergized hearts, an inverse relationship between cytosolic energy level and caffeine-mobilized 45Ca pool size was observed. Thus, caffeine-induced 45Ca release was decreased 60% by pyruvate energization and increased 2.5-fold by substrate-free deenergization. Taken together, these results support the hypothesis that enhancement of myocardial inotropism by energy-yielding substrate is mediated by increased sarcoplasmic reticular Ca2+ loading/release. Thus we propose that the known control of sarcoplasmic reticular Ca2+ turnover by the protein kinase/phospholamban system can be modulated by cytosolic energy level.

AB - Myocardial contractile performance is a function of sarcoplasmic reticular Ca2+ uptake and release, Ca2+ handling is ATP-dependent and can account for up to 40% of total myocardial energy expenditure. We tested the hypothesis that the thermodynamics of the cytosolic adenylate system can modulate sarcoplasmic reticular Ca2+ handling and hence function in intact heart. Cellular energy level was experimentally manipulated by perfusing isolated working guinea-pig hearts with substrate-free medium or media fortified with lactate and/or pyruvate as the main energy substrate. Left ventricular contractile function was judged by stroke work and intraventricular dP dt. Cytosolic energy level was indexed by measured creatine kinase reactants. Relative to 5 mM lactate, 5 mM pyruvate increased left ventricular stroke work, dP dtmax, and dP dtmin, while lowering left ventricular end-diastolic pressure at physiological left atrial and aortic pressures. Pyruvate also doubled cytosolic phosphorylation potentials and increased [ATP] [ADP] ratio; this energetic enhancement distinguishes pyruvate from inotropic stimulation by catecholamines, which are known to decrease cytosolic energy level in perfused heart. Sarcoplasmic reticular Ca2+ handling was assessed in hearts prelabeled with 45Ca, subjected to 45Ca washout in the presence of different cytosolic energy levels, then stimulated with 10 mM caffeine to release residual sarcoplasmic reticular 45Ca. When ryanodine (1 μM) was applied to open Ca2+ channels and thereby released 45Ca from the sarcoplasmic reticulum during washout, caffeine-stimulated 45Ca release was decreased 96%, demonstrating that virtually the entire caffeine-sensitive 45Ca pool was located in the sarcoplasmic reticulum. In detailed comparisons of pyruvate-energized vs. substrate-free deenergized hearts, an inverse relationship between cytosolic energy level and caffeine-mobilized 45Ca pool size was observed. Thus, caffeine-induced 45Ca release was decreased 60% by pyruvate energization and increased 2.5-fold by substrate-free deenergization. Taken together, these results support the hypothesis that enhancement of myocardial inotropism by energy-yielding substrate is mediated by increased sarcoplasmic reticular Ca2+ loading/release. Thus we propose that the known control of sarcoplasmic reticular Ca2+ turnover by the protein kinase/phospholamban system can be modulated by cytosolic energy level.

KW - ATPase, Ca-

KW - Caffeine

KW - Cytosolic phosphorylation potential

KW - Pyruvate

KW - Ryanodine

KW - Sarcoplasmic reticulum

KW - Ventricular myocardium

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