The rise of [Na+]i during ischemia and reperfusion in the rat heart-underlying mechanisms

Intracellular Na+ concentration ([Na+](i)) rises in the heart during ischemia, and on reperfusion, there is a transient rise followed by a return toward control. These changes in [Na+](i) contribute to ischemic and reperfusion damage through their effects on Ca(2+)overload. Part of the rise of [Na+](i) during ischemia may be caused by increased activity of the cardiac Na+/H+ exchanger (NHE1), activated by the ischemic rise in [H+](i). In support of this view, NHE1 inhibitors reduce the [Na+](i) rise during ischemia. Another possibility is that the rise of [Na+](i) during ischemia is caused by Na+ influx through channels. We have reexamined these issues by use of two different NHE1 inhibitors, amiloride, and zoniporide, in addition to tetrodotoxin (TTX), which blocks voltage-sensitive Na+ channels. All three drugs produced cardioprotection after ischemia, but amiloride (100 mu M) and TTX (300 nM) prevented the rise in [Na+](i) during ischemia, whereas zoniporide (100 nM) did not. Both amiloride and zoniporide prevented the rise of [Na+](i) on reperfusion, whereas TTX was without effect. In an attempt to explain these differences, we measured the ability of the three drugs to block Na+ currents. At the concentrations used, TTX reduced the transient Na+ current (I (Na)) by 11 +/- 2% while amiloride and zoniporide were without effect. In contrast, TTX largely eliminated the persistent Na+ current (I (Na,P)) and amiloride was equally effective, whereas zoniporide had a substantially smaller effect reducing I (Na,P) to 41 +/- 8%. These results suggest that part of the effect of NHE1 inhibitors on the [Na+](i) during ischemia is by blockade of I (Na,P). The fact that a low concentration of TTX eliminated the rise of [Na+](i) during ischemia suggests that I (Na,P) is a major source of Na+ influx in this model of ischemia.