Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1093/cvr/cvu251

Type

Journal article

Journal

Cardiovasc Res

Publication Date

01/02/2015

Volume

105

Pages

171 - 181

Keywords

Acidosis, Calcium, Diffusion, E–C coupling, Na+–H+ exchange, Animals, Calcium, Heart Ventricles, Hydrogen-Ion Concentration, Intracellular Space, Ions, Myocardial Contraction, Myocytes, Cardiac, Rats, Sarcoplasmic Reticulum, Sodium