Nifedipine and diltiazem suppress ventricular arrhythmogenesis and calcium release in mouse hearts

Richard Balasubramaniam, Sangeeta Chawla, Lauren Mackenzie, Christof J Schwiening, Andrew A Grace, Christopher L-H Huang

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Ventricular arrhythmogenesis leading to sudden cardiac death remains responsible for significant mortality in conditions such as cardiac failure and the long-QT syndrome (LQTS). Arrhythmias may be accentuated by beta-adrenergic stimulation and, accordingly, the present study explored the possible effects of beta-adrenergic stimulation and L-type Ca(2+) channel blockade on ventricular arrhythmogenesis and Ca(2+) handling using the mouse heart as an experimental system. Studies in whole, Langendorff-perfused hearts using programmed electrical stimulation protocols adapted from clinical practice demonstrated sustained ventricular tachycardia following addition of 0.1 microM isoprenaline (n=15), whilst no arrhythmias were observed in the absence of the drug (n=15). Arrhythmias were suppressed by nifedipine or diltiazem pre-treatment (both 1 microM) (n=8 and 4 respectively) and were also induced by elevating external [Ca(2+)] (n=3). At the cellular level, 0.1 microM isoprenaline significantly increased normalized fluorescence (F/F(0)) in field-stimulated fluo-3-loaded mouse ventricular myocytes imaged using confocal microscopy, reflecting increases in sarcoplasmic reticulum Ca(2+) release (n=8). Elevated external [Ca(2+)] also increased F/F(0) (n=4) whilst 0.1 microM nifedipine or 0.1 microM diltiazem significantly decreased F/F(0) (n=13 and 6 respectively). Pre-treatment with 0.1 microM nifedipine or 0.1 microM diltiazem suppressed the increases in F/F(0) induced by 0.1 microM isoprenaline alone (n=14 and 6 respectively). The findings thus paralleled suppression of isoprenaline-induced arrhythmias seen with nifedipine or diltiazem at the whole-heart level. Taken together, the findings may have implications for the use of L-type Ca(2+) channel blockade in conditions associated with beta-adrenergically driven ventricular arrhythmias such as cardiac failure and LQTS.
Original languageEnglish
Pages (from-to)150-8
Number of pages9
JournalPflügers Archiv : European journal of physiology
Issue number2
Publication statusPublished - 2004


  • Adrenergic beta-Agonists
  • Animals
  • Anti-Arrhythmia Agents
  • Calcium
  • Calcium Channel Blockers
  • Cytosol
  • Diltiazem
  • Electric Stimulation
  • Heart
  • Isoproterenol
  • Mice
  • Mice, Inbred Strains
  • Myocytes, Cardiac
  • Nifedipine
  • Tachycardia, Ventricular

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