Details

Autor(en) / Beteiligte

• Torres, Natalia S.
• Larbig, Robert
• Rock, Alex
• Goldhaber, Joshua I.
• Bridge, John H. B.

Titel

Na+ currents are required for efficient excitation–contraction coupling in rabbit ventricular myocytes: a possible contribution of neuronal Na+ channels

Ist Teil von

• The Journal of physiology, 2010-11, Vol.588 (21), p.4249-4260

Ort / Verlag

Oxford, UK: Blackwell Publishing Ltd

Erscheinungsjahr

2010

Quelle

Access via Wiley Online Library

Beschreibungen/Notizen

• Ca2+ transients were activated in rabbit ventricular cells by a sequence of action potential shaped voltage clamps. After activating a series of control transients, Na+ currents (INa) were inactivated with a ramp from −80 to −40 mV (1.5 s) prior to the action potential clamp. The transients were detected with the calcium indicator Fluo‐4 and an epifluorescence system. With zero Na+ in the pipette INa inactivation produced a decline in the SR Ca2+ release flux (measured as the maximum rate of rise of the transient) of 27 ± 4% (n= 9, P < 0.001) and a peak amplitude reduction of 10 ± 3% (n= 9, P < 0.05). With 5 mm Na+ in the pipette the reduction in release flux was greater (34 ± 4%, n= 4, P < 0.05). The ramp effectively inactivates INa without changing ICa, and there was no significant change in the transmembrane Ca2+ flux after the inactivation of INa. We next evoked action potentials under current clamp. TTX at 100 nm, which selectively blocks neuronal isoforms of Na+ channels, produced a decline in SR Ca2+ release flux of 35 ± 3% (n= 6, P < 0.001) and transient amplitude of 12 ± 2% (n= 6, P < 0.05). This effect was similar to the effect of INa inactivation on release flux. We conclude that a TTX‐sensitive INa is essential for efficient triggering of SR Ca2+ release. We propose that neuronal Na+ channels residing within couplons activate sufficient reverse Na+–Ca2+ exchanger (NCX) to prime the junctional cleft with Ca2+. The results can be explained if non‐linearities in excitation–contraction coupling mechanisms modify the coupling fidelity of ICa, which is known to be low at positive potentials. The hypothesis that the sodium–calcium exchanger activated by sodium current is involved in the process of excitation–contraction coupling in cardiac ventricular myocytes is controversial. We show in this paper that, at least in rabbits, the sodium current makes a significant contribution to triggering sarcoplasmic reticulum calcium release in ventricular cells by activating a reverse sodium–calcium exchanger. It appears that neuronal sodium current is involved in mediating this effect. We propose for the first time a mechanism of excitation–contraction coupling that is subject to regulation. Among other things this mechanism reduces the probability of triggered calcium release during the diastolic interval when it could produce triggered arrhythmias.