Intracellular [Na +] modulates synergy between Na +/Ca 2+ exchanger and L-type Ca 2+ current in cardiac excitation-contraction coupling during action potentials

Rafael J. Ramirez, Rajan Sah, Jie Liu, Robert A. Rose, Peter H. Backx

Research output: Contribution to journalArticle

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Excitation-contraction coupling (ECC) in cardiac myocytes involves triggering of Ca 2+ release from the sarcoplasmic reticulum (SR) by L-type Ca channels, whose activity is strongly influenced by action potential (AP) profile. The contribution of Ca 2+ entry via the Na +/Ca 2+ exchanger (NCX) to trigger SR Ca 2+ release during ECC in response to an AP remains uncertain. To isolate the contribution of NCX to SR Ca 2+ release, independent of effects on SR Ca 2+ load, Ca 2+ release was determined by recording Ca 2+ spikes using confocal microscopy on patch-clamped rat ventricular myocytes with [Ca 2+] i fixed at 150 nmol/L. In response to AP clamps, normalized Ca 2+ spike amplitudes (ΔF/F 0) increased sigmoidally and doubled as [Na +] i was elevated from 0 to 20 mmol/L with an EC 50 of ∼10 mmol/L. This [Na +] i-dependence was independent of I Na as well as SR Ca 2+ load, which was unchanged under our experimental conditions. However, NCX inhibition using either KB-R7943 or XIP reduced ΔF/F 0 amplitude in myocytes with 20 mmol/L [Na +] i, but not with 5 mmol/L [Na +] i. SR Ca 2+ release was complete before the membrane repolarized to-15 mV, indicating Ca 2+ entry into the dyad (not reduced extrusion) underlies [Na +] i-dependent enhancement of ECC. Because I Ca,L inhibition with 50 mmol/L Cd 2+ abolished Ca 2+ spikes, our results demonstrate that during cardiac APs, NCX enhances SR Ca 2+ release by synergistically increasing the efficiency of I Ca,L-mediated ECC.

Original languageEnglish
Pages (from-to)967-977
Number of pages11
JournalBasic Research in Cardiology
Issue number6
StatePublished - Nov 1 2011
Externally publishedYes


  • Ca spike
  • Cardiac excitation-contraction coupling
  • Na /Ca exchanger

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