Na⁺ ions as spatial intracellular messengers for co-ordinating Ca²⁺ signals during pH heterogeneity in cardiomyocytes

Cardiovasc Res. 2015 Feb 1;105(2):171-81. doi: 10.1093/cvr/cvu251. Epub 2014 Dec 16.


Aims: Contraction of the heart is regulated by electrically evoked Ca(2+) transients (CaTs). H(+) ions, the end products of metabolism, modulate CaTs through direct interactions with Ca(2+)-handling proteins and via Na(+)-mediated coupling between acid-extruding proteins (e.g. Na(+)/H(+) exchange, NHE1) and Na(+)/Ca(2+) exchange. Restricted H(+) diffusivity in cytoplasm predisposes pH-sensitive Ca(2+) signalling to becoming non-uniform, but the involvement of readily diffusible intracellular Na(+) ions may provide a means for combatting this.

Methods and results: CaTs were imaged in fluo3-loaded rat ventricular myocytes paced at 2 Hz. Cytoplasmic [Na(+)] ([Na(+)]i) was imaged using SBFI. Intracellular acidification by acetate exposure raised diastolic and systolic [Ca(2+)] (also observed with acid-loading by ammonium prepulse or CO₂ exposure). The systolic [Ca(2+)] response correlated with a rise in [Na(+)]i and sarcoplasmic reticulum Ca(2+) load, and was blocked by the NHE1 inhibitor cariporide (CO₂/HCO₃(-)-free media). Exposure of one half of a myocyte to acetate using dual microperfusion (CO₂/HCO₃(-)-free media) raised diastolic [Ca(2+)] locally in the acidified region. Systolic [Ca(2+)] and CaT amplitude increased more uniformly along the length of the cell, but only when NHE1 was functional. Cytoplasmic Na(+) diffusivity (DNa) was measured in quiescent cells, with strophanthidin present to inhibit the Na(+)/K(+) pump. With regional acetate exposure to activate a local NHE-driven Na(+)-influx, DNa was found to be sufficiently fast (680 µm(2)/s) for transmitting the pH-systolic Ca(2+) interaction over long distances.

Conclusions: Na(+) ions are rapidly diffusible messengers that expand the spatial scale of cytoplasmic pH-CaT interactions, helping to co-ordinate global Ca(2+) signalling during conditions of intracellular pH non-uniformity.

Keywords: Acidosis; Calcium; Diffusion; E–C coupling; Na+–H+ exchange.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Heart Ventricles / metabolism*
  • Hydrogen-Ion Concentration
  • Intracellular Space / metabolism
  • Ions / metabolism
  • Myocardial Contraction / physiology*
  • Myocytes, Cardiac / metabolism*
  • Rats
  • Sarcoplasmic Reticulum / metabolism
  • Sodium / metabolism*


  • Ions
  • Sodium
  • Calcium