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

Research output: Contribution to journalArticle

16 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 (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
Pages (from-to)1125-1132
Number of pages8
JournalHeart Rhythm
Volume9
Issue number7
DOIs
StatePublished - 1 Jul 2012

Keywords

  • Action potentials
  • Antiarrhythmic agents
  • Calcium
  • Depolarization

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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