© 2000 American Heart Association, Inc.
Cellular Biology |
Sarcoplasmic Reticulum Ca2+ Release Causes Myocyte Depolarization
Underlying Mechanism and Threshold for Triggered Action Potentials
From the Department of Physiology, Loyola University Medical Center, Maywood, Ill.
Correspondence to Donald M. Bers, PhD, Department of Physiology, Loyola University Medical Center, 2160 South First Ave, Maywood, IL 60153. E-mail dbers{at}luc.edu\\ © 2000 American Heart Association, Inc.
Abstract—Spontaneous
sarcoplasmic reticulum (SR) Ca2+ release
causes delayed afterdepolarizations (DADs) via
Ca2+-induced transient inward currents
(Iti). 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
[Ca2+]i (simple
exponential), and the
[Ca2+]i
threshold of 424±58 nmol/L was sufficient to trigger an AP. Blocking
Na+-Ca2+ exchange
current (INa/Ca) by removal of
[Na]o and
[Ca2+]o (or with 5
mmol/L Ni2+) reduced cDADs by >90%, for
the same
[Ca2+]i. In
contrast, blockade of Ca2+-activated
Cl– current
(ICl(Ca)) with 50 µmol/L
niflumate did not significantly alter cDADs. We conclude that DADs are
almost entirely due to INa/Ca,
not ICl(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
Itis with different time
courses, revealed that faster
Itis require less charge for AP
triggering. Given that spontaneous SR Ca2+
release occurs in waves, which are slower than cDADs or fast
Itis, the true
[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.
Key Words: delayed afterdepolarization • sarcoplasmic reticulum • transient inward current • Na+-Ca2+ exchanger • arrhythmia
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