Regulation of systolic [Ca2+]i and cellular Ca2+ flux balance in rat ventricular myocytes by SR Ca2+, L‐type Ca2+ current and diastolic [Ca2+]i

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Abstract
The force–frequency response is an important physiological mechanism regulating cardiac output changes and is accompanied in vivo by β‐adrenergic stimulation. We sought to determine the role of sarcoplasmic reticulum (SR) Ca2+ content and L‐type current (ICa‐L) in the frequency response of the systolic Ca2+ transient alone and during β‐adrenergic stimulation. Experiments (on single rat ventricular myocytes) were designed to be as physiological as possible. Under current clamp stimulation SR Ca2+ content increased in line with stimulation frequency (1–8 Hz) but the systolic Ca2+ transient was maximal at 6 Hz. Under voltage clamp, increasing frequency decreased both systolic Ca2+ transient and ICa‐L. Normalizing peak ICa‐L by altering the test potential decreased the Ca2+ transient amplitude less than an equivalent reduction achieved through changes in frequency. This suggests that, in addition to SR Ca2+ content and ICa‐L, another factor, possibly refractoriness of Ca2+ release from the SR contributes. Under current clamp, β‐adrenergic stimulation (isoprenaline, 30 nm) increased both the Ca2+ transient and the SR Ca2+ content and removed the dependence of both on frequency. In voltage clamp experiments, β‐adrenergic stimulation still increased SR Ca2+ content yet there was an inverse relation between frequency and Ca2+ transient amplitude and ICa‐L. Diastolic [Ca2+]i increased with stimulation frequency and this contributed substantially (69.3 ± 6% at 8 Hz) to the total Ca2+ efflux from the cell. We conclude that Ca2+ flux balance is maintained by the combination of increased efflux due to elevated diastolic [Ca2+]i and a decrease of influx on ICa‐L on each pulse.

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