Baartscheer A, Schumacher C A, Belterman C N W, Coronel R, Fiolet J W T
Experimental and Molecular Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Cardiovasc Res. 2003 Mar 15;57(4):986-95. doi: 10.1016/s0008-6363(02)00848-9.
Diastolic calcium is increased in myocytes from failing hearts despite up-regulation of the principal calcium extruding mechanism the Na+/Ca2+-exchanger (NCX). We hypothesize that increased diastolic calcium ([Ca2+]i) is secondary to increased cytosolic sodium ([Na+]i) and decreased driving force of NCX (DeltaG(exch)).
The stimulation rate dependence of simultaneously measured cytosolic sodium ([Na+]i), calcium transients ([Ca2+]i) and action potentials were determined with SBFI, indo-1 and the perforated patch technique in midmural left ventricular myocytes isolated from rabbits with pressure and volume overload induced heart failure (HF) and in age matched controls. Dynamic changes of DeltaG(exch) were calculated.
With increasing stimulation frequency, 0.2-3 Hz (all data HF versus control): [Na+]i increased (6.4 to 10.8 versus 3.8 to 6.4 mmol/l), diastolic [Ca2+]i increased (142 to 219 versus 47 to 98 nmol/l), calcium transient amplitude decreased in HF (300 to 250 nmol/l) but increased in control (201 to 479 nmol/l), action potential duration (APD90) decreased (380 to 260 versus 325 to 205 ms) and time averaged DeltaG(exch) decreased (6.8 to 2.8 versus 8.7 to 6.4 kJ/mol. With increasing stimulation rate the forward mode time integral of DeltaG(exch) decreased in HF by about 30%, the reversed mode time integral increased about ninefold and the duration of reversed mode operation more than sixfold relative to control.
[Na+]i is increased in HF and the driving force of NCX is decreased. NCX exerts thermodynamic control over diastolic calcium. Disturbed diastolic calcium handling in HF is due to decreased forward mode DeltaG(exch) secondary to increased [Na+]i and prolongation of the action potential. Enhanced reversed mode DeltaG(exch) may account for increased contribution of NCX to e-c coupling in HF.
尽管心脏主要的钙外排机制钠/钙交换体（NCX）上调，但衰竭心脏的心肌细胞舒张期钙仍升高。我们推测舒张期钙浓度（[Ca2+]i）升高继发于胞质钠浓度（[Na+]i）升高以及NCX驱动力（ΔG(exch)）降低。
采用SBFI、indo-1和穿孔膜片钳技术，测定从压力和容量超负荷诱导的心力衰竭（HF）兔及年龄匹配的对照兔分离的左心室中层心肌细胞中同时测量的胞质钠（[Na+]i）、钙瞬变（[Ca2+]i）和动作电位的刺激频率依赖性。计算ΔG(exch)的动态变化。
随着刺激频率增加，0.2 - 3 Hz（所有数据为HF组与对照组对比）：[Na+]i升高（6.4至10.8 mmol/l对比3.8至6.4 mmol/l），舒张期[Ca2+]i升高（142至219 nmol/l对比47至98 nmol/l），HF组钙瞬变幅度降低（300至250 nmol/l）而对照组升高（201至479 nmol/l），动作电位时程（APD90）降低（380至260 ms对比325至205 ms），时间平均ΔG(exch)降低（6.8至2.8 kJ/mol对比8.7至6.4 kJ/mol）。随着刺激频率增加，HF组中ΔG(exch)的正向模式时间积分降低约30%，反向模式时间积分增加约9倍，反向模式运行持续时间相对于对照组增加超过6倍。
HF组中[Na+]i升高且NCX驱动力降低。NCX对舒张期钙发挥热力学控制作用。HF时舒张期钙处理紊乱是由于[Na+]i升高和动作电位延长导致正向模式ΔG(exch)降低所致。增强的反向模式ΔG(exch)可能解释了HF时NCX对兴奋 - 收缩偶联的贡献增加。
