Systolic [Ca2+]i regulates diastolic levels in rat ventricular myocytes

Abstract

[Ca²⁺]_i must be low enough in diastole so that the ventricle is relaxed and can refill with blood. Interference with this will impair relaxation. The factors responsible for regulation of diastolic [Ca²⁺]_i, in particular the relative roles of the sarcoplasmic reticulum (SR) and surface membrane are unclear. We investigated the effects on diastolic [Ca²⁺]_i that result from the changes of Ca cycling known to occur in heart failure. Experiments were performed using Fluo-3 in voltage-clamped rat ventricular myocytes. Increasing stimulation frequency increased diastolic [Ca²⁺]_i. This increase of [Ca²⁺]_i was larger when SR function was impaired either by making the RyR leaky (with caffeine or ryanodine) or by decreasing SERCA activity with thapsigargin. The increase of diastolic [Ca²⁺]_i produced by interfering with the SR was accompanied by a decrease of the amplitude of the systolic Ca transient such that there was no change of time-averaged [Ca²⁺]_i. Time-averaged [Ca²⁺]_i was increased by β-adrenergic stimulation with isoprenaline and increased in a saturating manner with increased stimulation frequency; average [Ca²⁺]_i was a linear function of Ca entry per unit time. Diastolic and time-averaged [Ca²⁺]_i were decreased by decreasing the L-type Ca current (with 50 μm cadmium chloride). We conclude that diastolic [Ca²⁺]_i is controlled by the balance between Ca entry and efflux during systole. Furthermore, manoeuvres which decrease the amplitude of the Ca transient (without decreasing Ca influx) will therefore increase diastolic [Ca²⁺]_i. This identifies a novel mechanism whereby changes of the amplitude of the systolic Ca transient control diastolic [Ca²⁺]_i.

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