Sodium influx via a non-selective pathway activated by the removal of extracellular divalent cations: possible role in the calcium paradox

Objective: Cation non-selective conductances which are induced upon removal of extracellular divalent cations have been identified in cardiac and other cells. We have examined whether the conductance identified in cardiac myocytes mediates an increase in intracellular Na+ (Na-i(+)) and have tested the ability of drugs to prevent this influx. Methods: Rat single ventricular myocytes at 22 degrees C were voltage-clamped in whole-cell mode to measure membrane currents or were loaded with SBFI to measure Na-i(+). Results: Removal of extracellular Ca2+ (Ca-o(2+)) and Mg2+ (Mg-o(2+)), which induced a current with reversal potential of -10 mV, also caused an increase in SBFI fluorescence ratio (340/380 nm). These changes were reversible on repletion of Ca-o(2+) and/or Mg-o(2+). They could not be prevented by nifedipine, indicating that they were not mediated by L-type Ca2+ channels. Both increases in non-selective conductance and in Na-i(+) were prevented by trivalent cations (Dy-o(3+), Gd-o(3+) or La-o(3+); 100 mu M) or reduced by the aminoglycoside gentamicin. Conclusion: A cation non-selective conductance, different from L-type Ca2+ channels, contributes to the Na-i(+) accumulation obtained during perfusion with Ca2+/Mg2+-free media, hence also to the Ca-i(2+) overload and cellular damage upon Ca-o(2+) repletion (the Ca2+ paradox). (C) 1999 Elsevier Science B.V. All rights reserved.