title: Na⁺ ions as spatial intracellular messengers for co-ordinating Ca²⁺ signals during pH heterogeneity in cardiomyocytes.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, Oxford, UK.
authors.forename: Pawel
authors.initials: P
authors.lastname: Swietach
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, Salt Lake City, UT, USA.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Spitzer
authors.affiliation: Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, Oxford, UK richard.vaughan-jones@dpag.ox.ac.uk.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Vaughan-Jones
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D042541:Intracellular Space / Q000378:metabolism; D007477:Ions / Q000378:metabolism; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*
chemical_list: D007477:Ions; D012964:Sodium; D002118:Calcium
keywords: Acidosis; Calcium; Diffusion; E–C coupling; Na+–H+ exchange