Protection Against Myocardial Ischemic/Reperfusion Injury by Inhibitors of Two Separate Pathways of Na+Entry

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+imay be a critical factor in ischemic cardioprotection.