Ranolazine decreases mechanosensitivity of the voltage-gated sodium ion channel NaV1.5: A novel mechanism of drug action

Arthur Beyder, Peter R. Strege, Santiago Reyes, Cheryl E. Bernard, Andre Terzic, Jonathan Makielski, Michael John Ackerman, Gianrico Farrugia

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Background-NaV1.5 is a mechanosensitive voltage-gated sodium-selective ion channel responsible for the depolarizing current and maintenance of the action potential plateau in the heart. Ranolazine is a NaV1.5 antagonist with antianginal and antiarrhythmic properties. Methods and Results- Mechanosensitivity of NaV1.5 was tested in voltage-clamped whole cells and cell-attached patches by bath flow and patch pressure, respectively. In whole cells, bath flow increased peak inward current in both murine ventricular cardiac myocytes (24±8%) and human embryonic kidney 293 cells heterologously expressing NaV1.5 (18±3%). The flow-induced increases in peak current were blocked by ranolazine. In cell-attached patches from cardiac myocytes and NaV1.5-expressing human embryonic kidney 293 cells, negative pressure increased NaV peak currents by 27±18% and 18±4% and hyperpolarized voltage dependence of activation by-11 mV and-10 mV, respectively. In human embryonic kidney 293 cells, negative pressure also increased the window current (250%) and increased late open channel events (250%). Ranolazine decreased pressure-induced shift in the voltage dependence (IC50 54 μmol/L) and eliminated the pressure-induced increases in window current and late current event numbers. Block of NaV1.5 mechanosensitivity by ranolazine was not due to the known binding site on DIVS6 (F1760). The effect of ranolazine on mechanosensitivity of NaV1.5 was approximated by lidocaine. However, ionized ranolazine and charged lidocaine analog (QX-314) failed to block mechanosensitivity. Conclusions-Ranolazine effectively inhibits mechanosensitivity of NaV1.5. The block of NaV1.5 mechanosensitivity by ranolazine does not utilize the established binding site and may require bilayer partitioning. Ranolazine block of NaV1.5 mechanosensitivity may be relevant in disorders of mechanoelectric dysfunction.

Original languageEnglish (US)
Pages (from-to)2698-2706
Number of pages9
JournalCirculation
Volume125
Issue number22
DOIs
StatePublished - Jun 5 2012

Fingerprint

Voltage-Gated Sodium Channels
Sodium Channels
Pharmaceutical Preparations
Pressure
Lidocaine
Baths
Kidney
Cardiac Myocytes
Binding Sites
Ranolazine
Action Potentials
Inhibitory Concentration 50
Maintenance

Keywords

  • Drugs
  • Electrophysiology
  • Ion channels
  • Mechanics
  • Myocytes
  • Pharmacology
  • Physiology

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Ranolazine decreases mechanosensitivity of the voltage-gated sodium ion channel NaV1.5 : A novel mechanism of drug action. / Beyder, Arthur; Strege, Peter R.; Reyes, Santiago; Bernard, Cheryl E.; Terzic, Andre; Makielski, Jonathan; Ackerman, Michael John; Farrugia, Gianrico.

In: Circulation, Vol. 125, No. 22, 05.06.2012, p. 2698-2706.

Research output: Contribution to journalArticle

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abstract = "Background-NaV1.5 is a mechanosensitive voltage-gated sodium-selective ion channel responsible for the depolarizing current and maintenance of the action potential plateau in the heart. Ranolazine is a NaV1.5 antagonist with antianginal and antiarrhythmic properties. Methods and Results- Mechanosensitivity of NaV1.5 was tested in voltage-clamped whole cells and cell-attached patches by bath flow and patch pressure, respectively. In whole cells, bath flow increased peak inward current in both murine ventricular cardiac myocytes (24±8{\%}) and human embryonic kidney 293 cells heterologously expressing NaV1.5 (18±3{\%}). The flow-induced increases in peak current were blocked by ranolazine. In cell-attached patches from cardiac myocytes and NaV1.5-expressing human embryonic kidney 293 cells, negative pressure increased NaV peak currents by 27±18{\%} and 18±4{\%} and hyperpolarized voltage dependence of activation by-11 mV and-10 mV, respectively. In human embryonic kidney 293 cells, negative pressure also increased the window current (250{\%}) and increased late open channel events (250{\%}). Ranolazine decreased pressure-induced shift in the voltage dependence (IC50 54 μmol/L) and eliminated the pressure-induced increases in window current and late current event numbers. Block of NaV1.5 mechanosensitivity by ranolazine was not due to the known binding site on DIVS6 (F1760). The effect of ranolazine on mechanosensitivity of NaV1.5 was approximated by lidocaine. However, ionized ranolazine and charged lidocaine analog (QX-314) failed to block mechanosensitivity. Conclusions-Ranolazine effectively inhibits mechanosensitivity of NaV1.5. The block of NaV1.5 mechanosensitivity by ranolazine does not utilize the established binding site and may require bilayer partitioning. Ranolazine block of NaV1.5 mechanosensitivity may be relevant in disorders of mechanoelectric dysfunction.",
keywords = "Drugs, Electrophysiology, Ion channels, Mechanics, Myocytes, Pharmacology, Physiology",
author = "Arthur Beyder and Strege, {Peter R.} and Santiago Reyes and Bernard, {Cheryl E.} and Andre Terzic and Jonathan Makielski and Ackerman, {Michael John} and Gianrico Farrugia",
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T1 - Ranolazine decreases mechanosensitivity of the voltage-gated sodium ion channel NaV1.5

T2 - A novel mechanism of drug action

AU - Beyder, Arthur

AU - Strege, Peter R.

AU - Reyes, Santiago

AU - Bernard, Cheryl E.

AU - Terzic, Andre

AU - Makielski, Jonathan

AU - Ackerman, Michael John

AU - Farrugia, Gianrico

PY - 2012/6/5

Y1 - 2012/6/5

N2 - Background-NaV1.5 is a mechanosensitive voltage-gated sodium-selective ion channel responsible for the depolarizing current and maintenance of the action potential plateau in the heart. Ranolazine is a NaV1.5 antagonist with antianginal and antiarrhythmic properties. Methods and Results- Mechanosensitivity of NaV1.5 was tested in voltage-clamped whole cells and cell-attached patches by bath flow and patch pressure, respectively. In whole cells, bath flow increased peak inward current in both murine ventricular cardiac myocytes (24±8%) and human embryonic kidney 293 cells heterologously expressing NaV1.5 (18±3%). The flow-induced increases in peak current were blocked by ranolazine. In cell-attached patches from cardiac myocytes and NaV1.5-expressing human embryonic kidney 293 cells, negative pressure increased NaV peak currents by 27±18% and 18±4% and hyperpolarized voltage dependence of activation by-11 mV and-10 mV, respectively. In human embryonic kidney 293 cells, negative pressure also increased the window current (250%) and increased late open channel events (250%). Ranolazine decreased pressure-induced shift in the voltage dependence (IC50 54 μmol/L) and eliminated the pressure-induced increases in window current and late current event numbers. Block of NaV1.5 mechanosensitivity by ranolazine was not due to the known binding site on DIVS6 (F1760). The effect of ranolazine on mechanosensitivity of NaV1.5 was approximated by lidocaine. However, ionized ranolazine and charged lidocaine analog (QX-314) failed to block mechanosensitivity. Conclusions-Ranolazine effectively inhibits mechanosensitivity of NaV1.5. The block of NaV1.5 mechanosensitivity by ranolazine does not utilize the established binding site and may require bilayer partitioning. Ranolazine block of NaV1.5 mechanosensitivity may be relevant in disorders of mechanoelectric dysfunction.

AB - Background-NaV1.5 is a mechanosensitive voltage-gated sodium-selective ion channel responsible for the depolarizing current and maintenance of the action potential plateau in the heart. Ranolazine is a NaV1.5 antagonist with antianginal and antiarrhythmic properties. Methods and Results- Mechanosensitivity of NaV1.5 was tested in voltage-clamped whole cells and cell-attached patches by bath flow and patch pressure, respectively. In whole cells, bath flow increased peak inward current in both murine ventricular cardiac myocytes (24±8%) and human embryonic kidney 293 cells heterologously expressing NaV1.5 (18±3%). The flow-induced increases in peak current were blocked by ranolazine. In cell-attached patches from cardiac myocytes and NaV1.5-expressing human embryonic kidney 293 cells, negative pressure increased NaV peak currents by 27±18% and 18±4% and hyperpolarized voltage dependence of activation by-11 mV and-10 mV, respectively. In human embryonic kidney 293 cells, negative pressure also increased the window current (250%) and increased late open channel events (250%). Ranolazine decreased pressure-induced shift in the voltage dependence (IC50 54 μmol/L) and eliminated the pressure-induced increases in window current and late current event numbers. Block of NaV1.5 mechanosensitivity by ranolazine was not due to the known binding site on DIVS6 (F1760). The effect of ranolazine on mechanosensitivity of NaV1.5 was approximated by lidocaine. However, ionized ranolazine and charged lidocaine analog (QX-314) failed to block mechanosensitivity. Conclusions-Ranolazine effectively inhibits mechanosensitivity of NaV1.5. The block of NaV1.5 mechanosensitivity by ranolazine does not utilize the established binding site and may require bilayer partitioning. Ranolazine block of NaV1.5 mechanosensitivity may be relevant in disorders of mechanoelectric dysfunction.

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KW - Electrophysiology

KW - Ion channels

KW - Mechanics

KW - Myocytes

KW - Pharmacology

KW - Physiology

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