Isoproterenol does not enhance Ca-dependent Na/Ca exchange current in intact rabbit ventricular myocytes

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Abstract

Cardiac Na/Ca exchange (NCX, NCX1.1) is critical in cardiac myocyte Ca regulation, and its altered function contributes to inotropic state, systolic dysfunction in heart failure and arrhythmogenesis. Regulation of NCX is multifaceted, but protein kinase A (PKA) effects on NCX function are controversial. Here, we use three different and complementary approaches to compare NCX function ± 1 μM isoproterenol (ISO) in intact rabbit cardiac myocytes (in paired comparisons). First, in field-stimulated intact cells we inferred the cytosolic [Ca] ([Ca]i) dependence of NCX function from the decay rate of caffeine-induced [Ca]i transients. Second, we measured caffeine-induced [Ca]i and inward INCX simultaneously (perforated patch voltage clamp), to measure directly the [Ca]i dependence of NCX rate. Third, using whole cell ruptured patch with [Ca]i heavily buffered to 100:nM, [Na]i = 10:mM, and ICa, SR Ca release and Na/K pump all blocked, we recorded I NCX ramps at 37°C. We find that NCX function is not altered by PKA activation under any of these three protocols, where intracellular conditions ranged from near-physiological to highly controlled. This does not rule out NCX modulation by PKA under all conditions, or in species other than rabbit. However, such effects are likely to be either minor (vs. other PKA actions on myocyte Ca handling) or indirect, such as secondary effects dependent on altered local [Ca]i and [Na]i.

Original languageEnglish (US)
Pages (from-to)972-981
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume39
Issue number6
DOIs
StatePublished - Dec 2005
Externally publishedYes

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Caffeine
Isoproterenol
Muscle Cells
Rabbits
Cyclic AMP-Dependent Protein Kinases
Cardiac Myocytes
Matched-Pair Analysis
Architectural Accessibility
Heart Failure

Keywords

  • Cardiac excitation-contraction coupling
  • Isoproterenol
  • Protein kinase A
  • Rabbit
  • Sodium-calcium exchange

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

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title = "Isoproterenol does not enhance Ca-dependent Na/Ca exchange current in intact rabbit ventricular myocytes",
abstract = "Cardiac Na/Ca exchange (NCX, NCX1.1) is critical in cardiac myocyte Ca regulation, and its altered function contributes to inotropic state, systolic dysfunction in heart failure and arrhythmogenesis. Regulation of NCX is multifaceted, but protein kinase A (PKA) effects on NCX function are controversial. Here, we use three different and complementary approaches to compare NCX function ± 1 μM isoproterenol (ISO) in intact rabbit cardiac myocytes (in paired comparisons). First, in field-stimulated intact cells we inferred the cytosolic [Ca] ([Ca]i) dependence of NCX function from the decay rate of caffeine-induced [Ca]i transients. Second, we measured caffeine-induced [Ca]i and inward INCX simultaneously (perforated patch voltage clamp), to measure directly the [Ca]i dependence of NCX rate. Third, using whole cell ruptured patch with [Ca]i heavily buffered to 100:nM, [Na]i = 10:mM, and ICa, SR Ca release and Na/K pump all blocked, we recorded I NCX ramps at 37°C. We find that NCX function is not altered by PKA activation under any of these three protocols, where intracellular conditions ranged from near-physiological to highly controlled. This does not rule out NCX modulation by PKA under all conditions, or in species other than rabbit. However, such effects are likely to be either minor (vs. other PKA actions on myocyte Ca handling) or indirect, such as secondary effects dependent on altered local [Ca]i and [Na]i.",
keywords = "Cardiac excitation-contraction coupling, Isoproterenol, Protein kinase A, Rabbit, Sodium-calcium exchange",
author = "Ginsburg, {Kenneth S} and Bers, {Donald M}",
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T1 - Isoproterenol does not enhance Ca-dependent Na/Ca exchange current in intact rabbit ventricular myocytes

AU - Ginsburg, Kenneth S

AU - Bers, Donald M

PY - 2005/12

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N2 - Cardiac Na/Ca exchange (NCX, NCX1.1) is critical in cardiac myocyte Ca regulation, and its altered function contributes to inotropic state, systolic dysfunction in heart failure and arrhythmogenesis. Regulation of NCX is multifaceted, but protein kinase A (PKA) effects on NCX function are controversial. Here, we use three different and complementary approaches to compare NCX function ± 1 μM isoproterenol (ISO) in intact rabbit cardiac myocytes (in paired comparisons). First, in field-stimulated intact cells we inferred the cytosolic [Ca] ([Ca]i) dependence of NCX function from the decay rate of caffeine-induced [Ca]i transients. Second, we measured caffeine-induced [Ca]i and inward INCX simultaneously (perforated patch voltage clamp), to measure directly the [Ca]i dependence of NCX rate. Third, using whole cell ruptured patch with [Ca]i heavily buffered to 100:nM, [Na]i = 10:mM, and ICa, SR Ca release and Na/K pump all blocked, we recorded I NCX ramps at 37°C. We find that NCX function is not altered by PKA activation under any of these three protocols, where intracellular conditions ranged from near-physiological to highly controlled. This does not rule out NCX modulation by PKA under all conditions, or in species other than rabbit. However, such effects are likely to be either minor (vs. other PKA actions on myocyte Ca handling) or indirect, such as secondary effects dependent on altered local [Ca]i and [Na]i.

AB - Cardiac Na/Ca exchange (NCX, NCX1.1) is critical in cardiac myocyte Ca regulation, and its altered function contributes to inotropic state, systolic dysfunction in heart failure and arrhythmogenesis. Regulation of NCX is multifaceted, but protein kinase A (PKA) effects on NCX function are controversial. Here, we use three different and complementary approaches to compare NCX function ± 1 μM isoproterenol (ISO) in intact rabbit cardiac myocytes (in paired comparisons). First, in field-stimulated intact cells we inferred the cytosolic [Ca] ([Ca]i) dependence of NCX function from the decay rate of caffeine-induced [Ca]i transients. Second, we measured caffeine-induced [Ca]i and inward INCX simultaneously (perforated patch voltage clamp), to measure directly the [Ca]i dependence of NCX rate. Third, using whole cell ruptured patch with [Ca]i heavily buffered to 100:nM, [Na]i = 10:mM, and ICa, SR Ca release and Na/K pump all blocked, we recorded I NCX ramps at 37°C. We find that NCX function is not altered by PKA activation under any of these three protocols, where intracellular conditions ranged from near-physiological to highly controlled. This does not rule out NCX modulation by PKA under all conditions, or in species other than rabbit. However, such effects are likely to be either minor (vs. other PKA actions on myocyte Ca handling) or indirect, such as secondary effects dependent on altered local [Ca]i and [Na]i.

KW - Cardiac excitation-contraction coupling

KW - Isoproterenol

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KW - Rabbit

KW - Sodium-calcium exchange

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