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 othe r cells. We have examined whether the conductance identified in cardiac myo cytes mediates an increase in intracellular Na+ (Na-i(+)) and have tested t he ability of drugs to prevent this influx. Methods: Rat single ventricular myocytes at 22 degrees C were voltage-clamped in whole-cell mode to measur e membrane currents or were loaded with SBFI to measure Na-i(+). Results: R emoval 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 SBF I fluorescence ratio (340/380 nm). These changes were reversible on repleti on 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 increa ses 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 amino glycoside gentamicin. Conclusion: A cation non-selective conductance, diffe rent from L-type Ca2+ channels, contributes to the Na-i(+) accumulation obt ained 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.