title: Na+ currents are required for efficient excitation-contraction coupling in rabbit ventricular myocytes: a possible contribution of neuronal Na+ channels.
abstract: 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.
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112-5000, USA.
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Torres
authors.forename: Robert
authors.initials: R
authors.lastname: Larbig
authors.forename: Alex
authors.initials: A
authors.lastname: Rock
authors.forename: Joshua I
authors.initials: JI
authors.lastname: Goldhaber
authors.forename: John H B
authors.initials: JH
authors.lastname: Bridge
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology*; D023421:Models, Animal; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D019831:Sodium-Calcium Exchanger / Q000187:drug effects / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D015222:Sodium Channels; D019831:Sodium-Calcium Exchanger; D013779:Tetrodotoxin; D002118:Calcium