Blocking the Late Sodium Current Reduces Intracellular Sodium Accumulation During Sodium Pump Inhibition

Abstract

Impairment of Na+/K+-ATPase activity reduces sodium efflux and leads to an increase in intracellular Na+ (Na+i). We tested the hypothesis that Na+ accumulation caused by ouabain, a Na+/K+-ATPase inhibitor, would be reduced by concurrent inhibition of the late sodium current (INaL). We measured Na+i, high energy phosphates, and chemical driving force (ΔG∼ATP) in isolated guinea pig hearts in real time with 23Na- and 31P- NMR. Hearts were pre-treated for 10 min with no drug (control) or with the INaL inhibitors ranolazine (Ran; 3, 10 μM) or tetrodotoxin (TTX, 1 μM), then additionally exposed for 60 min to ouabain (1.3 μM in 23Na- and 0.75 μM in 31P- NMR experiments), after which all drugs were washed out for 20 min. Na+i was not changed by TTX or Ran alone. However, Ran (10 μM) and TTX significantly attenuated effects of ouabain to increase Na+i and decrease ΔG∼ATP (see Figure). The findings suggest that INaL contributes significantly to Na+i accumulation during exposure of myocytes to cardiac glycosides.View Large Image | View Hi-Res Image | Download PowerPoint Slide