Previous work has demonstrated that drugs which inhibit Na+ entry through voltage-sensitive Na+ channels, or via Na(+)-H+ exchange protect the heart from ischemic reperfusion damage. The purpose of our study was to determine whether these drugs in combination will have an additive protective effect in Langendorff-perfused hearts. During reperfusion following 30 min of ischemia, developed tension and resting tension were 24 +/- 3 and 162 +/- 5%, respectively, of pre-ischemic values in non-treated ischemic hearts. The administration of HOE-642 to inhibit Na+/H+ exchange increased active developed tension (DT) to 58 +/- 2% of pre-ischemic levels and decreased resting tension (RT) to 111 +/- 3% of pre-ischemic levels. The administration of tetrodotoxin (TTX) to block the Na+ channel increased DT to 56 +/- 3% of the pre-ischemic level and reduced the RT to 126 +/- 12% of the pre-ischemic level. Together, HOE-642 and TTX increased recovery of DT to 63 +/- 2% of pre-ischemic levels and improved RT to 116 +/- 4% of pre-ischemic levels after 30 min of reperfusion. All drug treatment protocols significantly lowered the creatine phosphokinase activity measured in the coronary effluent in comparison to that observed in the non-treated hearts. These data demonstrate that inhibition of Na+ entry through either Na(+)-H+ exchange or the Na+ channel protects the heart from ischemic injury, but there is no additional benefit of blocking both routes of Na+ entry simultaneously. This suggests that a threshold level of Na+i may be a critical factor in ischemic cardioprotection.