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(Circulation Research. 1999;85:606-613.)
© 1999 American Heart Association, Inc.

Cellular Biology

Regulation of Ca²⁺ Homeostasis by Atypical Na⁺ Currents in Cultured Human Coronary Myocytes

Gilles Boccara¹, Cécile Choby¹, Jean Marc Frapier, Jean François Quignard, Joël Nargeot, Govindan Dayanithi, Sylvain Richard

From the Centre National de la Recherche Scientifique (G.B., C.C., J.F.Q., J.N., S.R.), Institut de Genetique Humaine; Service d'Anesthésie B et de Chirurgie Cardiovasculaire, Hôpital A. de Villeneuve (G.B., J.M.F.); and Centre National de la Recherche Scientifique UPR-9055 (G.D.), Montpellier, France.

Correspondence to Sylvain Richard, Laboratoire d'Electrophysiologie, CNRS-UPR 1142, Institut de Genetique Humaine, 141, Rue de la Cardonille, 34396 Montpellier Cedex 5, France. E-mail srichard{at}igh.cnrs.fr

Abstract—Primary cultured human coronary myocytes (HCMs) derived from ischemic human hearts express an atypical voltage-gated tetrodotoxin (TTX)-sensitive sodium current (I_Na). The whole-cell patch-clamp technique was used to study the properties of I_Na in HCMs. The variations of intracellular calcium ([Ca²⁺]_i) and sodium ([Na⁺]_i) were monitored in non–voltage-clamped cells loaded with Fura-2 or benzofuran isophthalate, respectively, using microspectrofluorimetry. The activation and steady-state inactivation properties of I_Na determined a "window" current between -50 and -10 mV suggestive of a steady-state Na⁺ influx at the cell resting membrane potential. Consistent with this hypothesis, the resting [Na⁺]_i was decreased by TTX (1 µmol/L). In contrast, it was increased by Na⁺ channel agonists that also promoted a large rise in [Ca²⁺]_i. Veratridine (10 µmol/L), toxin V from Anemonia sulcata (0.1 µmol/L), and N-bromoacetamide (300 µmol/L) increased [Ca²⁺]_i by 7- to 15-fold. This increase was prevented by prior application of TTX or lidocaine (10 µmol/L) and by the use of Na⁺-free or Ca²⁺-free external solutions. The Ca²⁺-channel antagonist nicardipine (5 µmol/L) blocked the effect of veratridine on [Ca²⁺]_i only partially. The residual component disappeared when external Na⁺ was replaced by Li⁺ known to block the Na⁺/Ca²⁺ exchanger. The resting [Ca²⁺]_i was decreased by TTX in some cells. In conclusion, I_Na regulates [Ca²⁺]_i in primary cultured HCMs. This regulation, effective at baseline, involves a tonic control of Ca²⁺ influx via depolarization-gated Ca²⁺ channels and, to a lesser extent, via a Na⁺/Ca²⁺ exchanger working in the reverse mode.

Key Words: vascular smooth muscle • persistent Na⁺ current • [Ca²⁺]_i • Ca²⁺ channel • Na⁺/Ca²⁺ exchanger

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