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Effect of intracellular Ca²⁺ and action potential duration on L-type Ca²⁺ channel inactivation and recovery from inactivation in rabbit cardiac myocytes

Department of Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois

Submitted 8 May 2006 ; accepted in final form 26 March 2007

Ca²⁺ current (I_Ca) recovery from inactivation is necessary for normal cardiac excitation-contraction coupling. In normal hearts, increased stimulation frequency increases force, but in heart failure (HF) this force-frequency relationship (FFR) is often flattened or reversed. Although reduced sarcoplasmic reticulum Ca²⁺-ATPase function may be involved, decreased I_Ca availability may also contribute. Longer action potential duration (APD), slower intracellular Ca²⁺ concentration ([Ca²⁺]_i) decline, and higher diastolic [Ca²⁺]_i in HF could all slow I_Ca recovery from inactivation, thereby decreasing I_Ca availability. We measured the effect of different diastolic [Ca²⁺]_i on I_Ca inactivation and recovery from inactivation in rabbit cardiac myocytes. Both I_Ca and Ba²⁺ current (I_Ba) were measured. I_Ca decay was accelerated only at high diastolic [Ca²⁺]_i (600 nM). I_Ba inactivation was slower but insensitive to [Ca²⁺]_i. Membrane potential dependence of I_Ca or I_Ba availability was not affected by [Ca²⁺]_i <600 nM. Recovery from inactivation was slowed by both depolarization and high [Ca²⁺]_i. We also used perforated patch with action potential (AP)-clamp and normal Ca²⁺ transients, using various APDs as conditioning pulses for different frequencies (and to simulate HF APD). Recovery of I_Ca following longer APD was increasingly incomplete, decreasing I_Ca availability. Trains of long APs caused a larger I_Ca decrease than short APD at the same frequency. This effect on I_Ca availability was exacerbated by slowing twitch [Ca²⁺]_i decline by 50%. We conclude that long APD and slower [Ca²⁺]_i decline lead to cumulative inactivation limiting I_Ca at high heart rates and might contribute to the negative FFR in HF, independent of altered Ca²⁺ channel properties.

calcium ion current; excitation-contraction coupling; calcium ion buffers

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