Sarcoplasmic reticulmn Ca2+ release causes myocyte depolarization: Underlying mechanism and threshold for triggered action potentials

Klaus Schlotthauer, Donald M Bers

Research output: Contribution to journalArticle

252 Scopus citations

Abstract

Spontaneous sarcoplasmic reticulum (SR) Ca2+ release causes delayed afterdepolarizations (DADs) via Ca2+-induced transient inward currents (I(ti)). However, no quantitative data exists regarding (1) Ca2+ dependence of DADs, (2) Ca2+ required to depolarize the cell to threshold and trigger an action potential (AP), or (3) relative contributions of Ca2+-activated currents to DADs. To address these points, we evoked SR Ca2+ release by rapid application of caffeine in indo 1-AM-loaded rabbit ventricular myocytes and measured caffeine-induced DADs (cDADs) with whole-cell current clamp. The SR Ca2+ load of the myocyte was varied by different AP frequencies. The cDAD amplitude doubled for every 88±8 nmol/L of Δ[Ca2+](i) (simple exponential), and the Δ[Ca2+](i) threshold of 424±58 nmol/L was sufficient to trigger an AP. Blocking Na+-Ca2+ exchange current (I(Na/Ca)) by removal of [Na](o) and [Ca2+](o) (or with 5 mmol/L Ni2+) reduced cDADs by >90%, for the same Δ[Ca2+](i). In contrast, blockade of Ca2+-activated Cl- current (I(Cl(Ca))) with 50 μmol/L niflumate did not significantly alter cDADs. We conclude that DADs are almost entirely due to I(Na/Ca), not I(Cl(Ca)) or Ca2+-activated nonselective cation current. To trigger an AP requires 30 to 40 μmol/L cytosolic Ca2+ or a [Ca2+](i) transient of 424 nmol/L. Current injection, simulating I(ti)s with different time courses, revealed that faster I(ti)s require less charge for AP triggering. Given that spontaneous SR Ca2+ release occurs in waves, which are slower than cDADs or fast I(ti)s, the true Δ[Ca2+](i) threshold for AP activation may be ≃3-fold higher in normal myocytes. This provides a safety margin against arrhythmia in normal ventricular myocytes.

Original languageEnglish (US)
Pages (from-to)774-780
Number of pages7
JournalCirculation Research
Volume87
Issue number9
StatePublished - Oct 27 2000
Externally publishedYes

Keywords

  • Arrhythmia
  • Delayed afterdepolarization
  • Na-Ca exchanger
  • Sarcoplasmic reticulum
  • Transient inward current

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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