Ryanodine receptor inhibition potentiates the activity of Na channel blockers against spontaneous calcium elevations and delayed afterdepolarizations in Langendorff-perfused rabbit ventricles

Young Soo Lee, Mitsunori Maruyama, Po Cheng Chang, Hyung Wook Park, Kyoung Suk Rhee, Yu Cheng Hsieh, Chia Hsiang Hsueh, Changyu Shen, Shien Fong Lin, Hyun Seok Hwang, Huiyong Yin, Björn C. Knollmann, Peng Sheng Chen

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

BACKGROUND: Na channel blockers are effective in suppressing delayed afterdepolarizations (DADs) in isolated Purkinje fibers. However, in isolated mouse ventricular myocytes lacking calsequestrin, only those Na channel blockers that also inhibit type 2 ryanodine receptor channels were effective against spontaneous Ca elevation (SCaE) and DADs. OBJECTIVE: To test the hypothesis that combined Na channel and type 2 ryanodine receptor channel blocker ((R)-propafenone) is more effective than a Na channel blocker (lidocaine) in suppressing SCaE and DADs in the intact rabbit ventricles. METHODS: We compared (R)-propafenone (3 μmol/L) with lidocaine (50 μmol/L) on SCaE and DADs by using epicardial optical mapping of intracellular calcium (Cai) and membrane voltage in Langendorff-perfused rabbit hearts. SCaE and DADs were induced by rapid pacing trains and isoproterenol (0.3 μmol/L) infusion. One arbitrary unit is equivalent to the Ca transient amplitude of paced beats. RESULTS: SCaEs were observed at the cessation of rapid pacing in all hearts at baseline. (R)-Propafenone nearly completely inhibited DADs and SCaE (0.04 arbitrary units [95% confidence interval 0.02-0.06] vs 0.23 arbitrary units [95% confidence interval 0.18-0.28] at baseline; n = 6 hearts; P <.001). Lidocaine also significantly reduced the SCaE but was significantly (P <.05) less effective than (R)-propafenone. Both drugs increased the rise time of action potential upstroke and reduced conduction velocity to a similar extent, suggesting a significant inhibition of INa. CONCLUSIONS: Both Na channel blockers significantly reduced tachycardia-induced SCaEs in the rabbit ventricles, but (R)-propafenone was significantly more effective than lidocaine. These data suggest that type 2 ryanodine receptor inhibition potentiates the activity of Na channel blockers against SCaE and DADs in the intact hearts.

Original languageEnglish (US)
Pages (from-to)1125-1132
Number of pages8
JournalHeart Rhythm
Volume9
Issue number7
DOIs
StatePublished - Jul 1 2012

Fingerprint

Propafenone
Ryanodine Receptor Calcium Release Channel
Lidocaine
Rabbits
Calcium
Epicardial Mapping
Calsequestrin
Confidence Intervals
Purkinje Fibers
Intracellular Membranes
Isoproterenol
Tachycardia
Muscle Cells
Action Potentials
Pharmaceutical Preparations

Keywords

  • Action potentials
  • Antiarrhythmic agents
  • Calcium
  • Depolarization

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Ryanodine receptor inhibition potentiates the activity of Na channel blockers against spontaneous calcium elevations and delayed afterdepolarizations in Langendorff-perfused rabbit ventricles. / Lee, Young Soo; Maruyama, Mitsunori; Chang, Po Cheng; Park, Hyung Wook; Rhee, Kyoung Suk; Hsieh, Yu Cheng; Hsueh, Chia Hsiang; Shen, Changyu; Lin, Shien Fong; Hwang, Hyun Seok; Yin, Huiyong; Knollmann, Björn C.; Chen, Peng Sheng.

In: Heart Rhythm, Vol. 9, No. 7, 01.07.2012, p. 1125-1132.

Research output: Contribution to journalArticle

Lee, Young Soo ; Maruyama, Mitsunori ; Chang, Po Cheng ; Park, Hyung Wook ; Rhee, Kyoung Suk ; Hsieh, Yu Cheng ; Hsueh, Chia Hsiang ; Shen, Changyu ; Lin, Shien Fong ; Hwang, Hyun Seok ; Yin, Huiyong ; Knollmann, Björn C. ; Chen, Peng Sheng. / Ryanodine receptor inhibition potentiates the activity of Na channel blockers against spontaneous calcium elevations and delayed afterdepolarizations in Langendorff-perfused rabbit ventricles. In: Heart Rhythm. 2012 ; Vol. 9, No. 7. pp. 1125-1132.
@article{df7ad006898544d59577bf595090c45f,
title = "Ryanodine receptor inhibition potentiates the activity of Na channel blockers against spontaneous calcium elevations and delayed afterdepolarizations in Langendorff-perfused rabbit ventricles",
abstract = "BACKGROUND: Na channel blockers are effective in suppressing delayed afterdepolarizations (DADs) in isolated Purkinje fibers. However, in isolated mouse ventricular myocytes lacking calsequestrin, only those Na channel blockers that also inhibit type 2 ryanodine receptor channels were effective against spontaneous Ca elevation (SCaE) and DADs. OBJECTIVE: To test the hypothesis that combined Na channel and type 2 ryanodine receptor channel blocker ((R)-propafenone) is more effective than a Na channel blocker (lidocaine) in suppressing SCaE and DADs in the intact rabbit ventricles. METHODS: We compared (R)-propafenone (3 μmol/L) with lidocaine (50 μmol/L) on SCaE and DADs by using epicardial optical mapping of intracellular calcium (Cai) and membrane voltage in Langendorff-perfused rabbit hearts. SCaE and DADs were induced by rapid pacing trains and isoproterenol (0.3 μmol/L) infusion. One arbitrary unit is equivalent to the Ca transient amplitude of paced beats. RESULTS: SCaEs were observed at the cessation of rapid pacing in all hearts at baseline. (R)-Propafenone nearly completely inhibited DADs and SCaE (0.04 arbitrary units [95{\%} confidence interval 0.02-0.06] vs 0.23 arbitrary units [95{\%} confidence interval 0.18-0.28] at baseline; n = 6 hearts; P <.001). Lidocaine also significantly reduced the SCaE but was significantly (P <.05) less effective than (R)-propafenone. Both drugs increased the rise time of action potential upstroke and reduced conduction velocity to a similar extent, suggesting a significant inhibition of INa. CONCLUSIONS: Both Na channel blockers significantly reduced tachycardia-induced SCaEs in the rabbit ventricles, but (R)-propafenone was significantly more effective than lidocaine. These data suggest that type 2 ryanodine receptor inhibition potentiates the activity of Na channel blockers against SCaE and DADs in the intact hearts.",
keywords = "Action potentials, Antiarrhythmic agents, Calcium, Depolarization",
author = "Lee, {Young Soo} and Mitsunori Maruyama and Chang, {Po Cheng} and Park, {Hyung Wook} and Rhee, {Kyoung Suk} and Hsieh, {Yu Cheng} and Hsueh, {Chia Hsiang} and Changyu Shen and Lin, {Shien Fong} and Hwang, {Hyun Seok} and Huiyong Yin and Knollmann, {Bj{\"o}rn C.} and Chen, {Peng Sheng}",
year = "2012",
month = "7",
day = "1",
doi = "10.1016/j.hrthm.2012.02.031",
language = "English (US)",
volume = "9",
pages = "1125--1132",
journal = "Heart Rhythm",
issn = "1547-5271",
publisher = "Elsevier",
number = "7",

}

TY - JOUR

T1 - Ryanodine receptor inhibition potentiates the activity of Na channel blockers against spontaneous calcium elevations and delayed afterdepolarizations in Langendorff-perfused rabbit ventricles

AU - Lee, Young Soo

AU - Maruyama, Mitsunori

AU - Chang, Po Cheng

AU - Park, Hyung Wook

AU - Rhee, Kyoung Suk

AU - Hsieh, Yu Cheng

AU - Hsueh, Chia Hsiang

AU - Shen, Changyu

AU - Lin, Shien Fong

AU - Hwang, Hyun Seok

AU - Yin, Huiyong

AU - Knollmann, Björn C.

AU - Chen, Peng Sheng

PY - 2012/7/1

Y1 - 2012/7/1

N2 - BACKGROUND: Na channel blockers are effective in suppressing delayed afterdepolarizations (DADs) in isolated Purkinje fibers. However, in isolated mouse ventricular myocytes lacking calsequestrin, only those Na channel blockers that also inhibit type 2 ryanodine receptor channels were effective against spontaneous Ca elevation (SCaE) and DADs. OBJECTIVE: To test the hypothesis that combined Na channel and type 2 ryanodine receptor channel blocker ((R)-propafenone) is more effective than a Na channel blocker (lidocaine) in suppressing SCaE and DADs in the intact rabbit ventricles. METHODS: We compared (R)-propafenone (3 μmol/L) with lidocaine (50 μmol/L) on SCaE and DADs by using epicardial optical mapping of intracellular calcium (Cai) and membrane voltage in Langendorff-perfused rabbit hearts. SCaE and DADs were induced by rapid pacing trains and isoproterenol (0.3 μmol/L) infusion. One arbitrary unit is equivalent to the Ca transient amplitude of paced beats. RESULTS: SCaEs were observed at the cessation of rapid pacing in all hearts at baseline. (R)-Propafenone nearly completely inhibited DADs and SCaE (0.04 arbitrary units [95% confidence interval 0.02-0.06] vs 0.23 arbitrary units [95% confidence interval 0.18-0.28] at baseline; n = 6 hearts; P <.001). Lidocaine also significantly reduced the SCaE but was significantly (P <.05) less effective than (R)-propafenone. Both drugs increased the rise time of action potential upstroke and reduced conduction velocity to a similar extent, suggesting a significant inhibition of INa. CONCLUSIONS: Both Na channel blockers significantly reduced tachycardia-induced SCaEs in the rabbit ventricles, but (R)-propafenone was significantly more effective than lidocaine. These data suggest that type 2 ryanodine receptor inhibition potentiates the activity of Na channel blockers against SCaE and DADs in the intact hearts.

AB - BACKGROUND: Na channel blockers are effective in suppressing delayed afterdepolarizations (DADs) in isolated Purkinje fibers. However, in isolated mouse ventricular myocytes lacking calsequestrin, only those Na channel blockers that also inhibit type 2 ryanodine receptor channels were effective against spontaneous Ca elevation (SCaE) and DADs. OBJECTIVE: To test the hypothesis that combined Na channel and type 2 ryanodine receptor channel blocker ((R)-propafenone) is more effective than a Na channel blocker (lidocaine) in suppressing SCaE and DADs in the intact rabbit ventricles. METHODS: We compared (R)-propafenone (3 μmol/L) with lidocaine (50 μmol/L) on SCaE and DADs by using epicardial optical mapping of intracellular calcium (Cai) and membrane voltage in Langendorff-perfused rabbit hearts. SCaE and DADs were induced by rapid pacing trains and isoproterenol (0.3 μmol/L) infusion. One arbitrary unit is equivalent to the Ca transient amplitude of paced beats. RESULTS: SCaEs were observed at the cessation of rapid pacing in all hearts at baseline. (R)-Propafenone nearly completely inhibited DADs and SCaE (0.04 arbitrary units [95% confidence interval 0.02-0.06] vs 0.23 arbitrary units [95% confidence interval 0.18-0.28] at baseline; n = 6 hearts; P <.001). Lidocaine also significantly reduced the SCaE but was significantly (P <.05) less effective than (R)-propafenone. Both drugs increased the rise time of action potential upstroke and reduced conduction velocity to a similar extent, suggesting a significant inhibition of INa. CONCLUSIONS: Both Na channel blockers significantly reduced tachycardia-induced SCaEs in the rabbit ventricles, but (R)-propafenone was significantly more effective than lidocaine. These data suggest that type 2 ryanodine receptor inhibition potentiates the activity of Na channel blockers against SCaE and DADs in the intact hearts.

KW - Action potentials

KW - Antiarrhythmic agents

KW - Calcium

KW - Depolarization

UR - http://www.scopus.com/inward/record.url?scp=84862887984&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84862887984&partnerID=8YFLogxK

U2 - 10.1016/j.hrthm.2012.02.031

DO - 10.1016/j.hrthm.2012.02.031

M3 - Article

C2 - 22387372

AN - SCOPUS:84862887984

VL - 9

SP - 1125

EP - 1132

JO - Heart Rhythm

JF - Heart Rhythm

SN - 1547-5271

IS - 7

ER -