Na/Ca exchange and contraction of the heart

Abstract

Sodium-calcium exchange (NCX) is the major calcium (Ca) efflux mechanism of ventricular cardiomyocytes. Consequently the exchanger plays a critical role in the regulation of cellular Ca content and hence contractility. Reductions in Ca efflux by the exchanger, such as those produced by elevated intracellular sodium (Na) in response to cardiac glycosides, raise sarcoplasmic reticulum (SR) Ca stores. The result is an increased Ca transient and cardiac contractility. Enhanced Ca efflux activity by the exchanger, for example during heart failure, may reduce diadic cleft Ca and excitation-contraction (EC) coupling gain. This aggravates the impaired contractility associated with SR Ca ATPase dysfunction and reduced SR Ca load in failing heart muscle. Recent data from our laboratories indicate that NCX can also impact the efficiency of EC coupling and contractility independent of SR Ca load through diadic cleft priming with Ca during the upstroke of the action potential. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes".

Keywords: AP; Ca; Calcium; EC; Excitation contraction coupling; Genetically modified mice; Heart contractility; Heart failure; KO; L-type Ca channels; LCCs; NCX; NCX knockout mouse; RyRs; SR; Sodium calcium exchanger; action potential; calcium; excitation–contraction coupling; ryanodine receptor; sarcoplasmic reticulum; sodium calcium exchanger.

Figure 1. Effects of ouabain on Ca transients in embryonic heart tubes isolated from wild type and NCX^−/− mice

In wildtype heart tubes loaded with the Ca indicator fura-2 (upper panels), 0.03 μM ouabain moderately increased Ca transients whereas 0.1 μM ouabain caused Ca overload. However in NCX^−/− heart tubes (lower panels) ouabain at either concentration had no effect, demonstrating that NCX is required for the effect of ouabain on Ca transients (modified from Reuter et al., Circ Res. 90, 305–308, 2002 and used with permission).

Figure 2. Reduced Excitation-Contraction Coupling Gain in NCX Homozygous Overexpressing Mice

Representative Ca currents (I_m) from wildtype (WT) and NCX homozygous overexpressing mice (HOM) are shown in A. Although the HOM Ca current is larger in the WT (summarized in C), the corresponding Ca transient (Δ[Ca²⁺]_i) measured with fura-2 (B) is smaller. The decreased Ca transient (summarized in D) in response to the increased current indicates a reduction in gain (E). (This figure was modified from Reuter et al., J Physiol. 554, 779–789, 2004, and used with permission [43]).

Figure 3. Effects of I_Na inactivation on Ca transients in WT and conditional NCX KO myocytes

Ca transients from a patch clamped wildtype (WT) ventricular myocyte before (A) and after (B) inactivating I_Na using a ramp prepulse. Note the decreased Ca transient after applying the inactivating prepulse (B). In contrast, the ramp prepulse has no effect in KO (C, D). Command voltage waveforms are shown in E (no prepulse) and F (prepulse). (Figure modified from Larbig et al. J Physiol. 588, 3267–3276 with permission [66]).

Figure 4. Effect of 100 nM TTX on Ca transient in isolated patch clamped rabbit myocytes

Representative Ca transients with and without 100 nM TTX present in the extracellular solution (A). The amplitude of the Ca transient decreased 12±2% (n=6) with TTX (summarized in B). *p<0.05. (modified from Torres et al. J Physiol. 588:4249–60. 2010 with permission [67]).