Sarcoplasmic Reticulum Ca 2+ Release Causes Myocyte Depolarization

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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 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 (INa/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 (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 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.

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