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

doi:10.1016/j.hrthm.2012.02.031

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^*

^*Corresponding author for this work

Department of Medicine

Indiana University Bloomington
Vanderbilt University

Research output: Contribution to journal › Journal article › peer-review

18 Scopus citations

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 (Ca_i) 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 I_Na. 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 language	English
Pages (from-to)	1125-1132
Number of pages	8
Journal	Heart Rhythm
Volume	9
Issue number	7
DOIs	https://doi.org/10.1016/j.hrthm.2012.02.031
State	Published - 2012.07

Keywords

Action potentials
Antiarrhythmic agents
Calcium
Depolarization

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10.1016/j.hrthm.2012.02.031

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Lee, Y. S., Maruyama, M., Chang, P. C., Park, H. W., Rhee, K. S., Hsieh, Y. C., Hsueh, C. H., Shen, C., Lin, S. F., Hwang, H. S., Yin, H., Knollmann, B. C., & Chen, P. S. (2012). Ryanodine receptor inhibition potentiates the activity of Na channel blockers against spontaneous calcium elevations and delayed afterdepolarizations in Langendorff-perfused rabbit ventricles. Heart Rhythm, 9(7), 1125-1132. https://doi.org/10.1016/j.hrthm.2012.02.031

@article{b56376c46f2e4a61b707dbb8ccb8739c,

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 = jul,

doi = "10.1016/j.hrthm.2012.02.031",

language = "English",

volume = "9",

pages = "1125--1132",

journal = "Heart Rhythm",

issn = "1547-5271",

number = "7",

}

Lee, YS, Maruyama, M, Chang, PC, Park, HW, Rhee, KS, Hsieh, YC, Hsueh, CH, Shen, C, Lin, SF, Hwang, HS, Yin, H, Knollmann, BC & Chen, PS 2012, 'Ryanodine receptor inhibition potentiates the activity of Na channel blockers against spontaneous calcium elevations and delayed afterdepolarizations in Langendorff-perfused rabbit ventricles', Heart Rhythm, vol. 9, no. 7, pp. 1125-1132. https://doi.org/10.1016/j.hrthm.2012.02.031

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 et al.
In: Heart Rhythm, Vol. 9, No. 7, 07.2012, p. 1125-1132.

Research output: Contribution to journal › Journal article › peer-review

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

Y1 - 2012/7

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 - https://www.scopus.com/pages/publications/84862887984

U2 - 10.1016/j.hrthm.2012.02.031

DO - 10.1016/j.hrthm.2012.02.031

M3 - Journal article

C2 - 22387372

AN - SCOPUS:84862887984

SN - 1547-5271

VL - 9

SP - 1125

EP - 1132

JO - Heart Rhythm

JF - Heart Rhythm

IS - 7

ER -

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

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Keywords

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