IMPROVED CARDIAC-FUNCTION AFTER PROLONGED HYPOTHERMIC ISCHEMIA WITH THE NA+ H+ EXCHANGE INHIBITOR HOE-694/

Background. Na+/H+ exchange represents an important mechanism for pH r egulation in the cardiac cell that, however, may paradoxically mediate tissue damage in the reperfused myocardium. We investigated whether i nhibition of the exchanger can protect the heart against damage after prolonged hypothermic storage with the use of the selective inhibitor 3-methylsulfony-4-piperidinobenzoyl-guanidine methanesulfonate (HOE 69 4). Methods. After equilibration, isolated rabbit hearts were arrested with a 3 minute infusion of modified St. Thomas' cardioplegic solutio n and subsequently maintained in ischemic arrest at 4 degrees C for 12 hours before reperfusion at 37 degrees C for 60 minutes. Left ventric ular function and creatine kinase release were measured at intervals t hroughout reperfusion. High-energy phosphate and adenine nucleotide co ntent were determined in hearts before cardioplegia, at the end of the 12-hour storage period, and at the end of reperfusion. HOE 694 (1 mu mol/L) was administered either with cardioplegia and throughout reperf usion (study 1) or selectively with either cardioplegia or reperfusion only (study 2). Results. In study 1, systolic function in untreated h earts recovered to less than 40% of preischemic values and was associa ted with a greater than 1,000% percent sustained elevation in left ven tricular end-diastolic pressure. In contrast, systolic recovery in HOE 694-treated hearts was significantly accelerated and improved to appr oximately 80%, whereas left ventricular end-diastolic pressure increas ed to only 300% of baseline. Significant protection also occurred in t hose hearts in which HOE 694 was administered only at reperfusion whil e the drug was less effective if given only during cardioplegia. Creat ine kinase release was not significantly affected except in study 2, w here it was significantly lower after 60 minutes of reperfusion in hea rts where HOE 694 was added at the time of reperfusion. Tissue metabol ite content was not affected by drug treatment. Conclusions. This stud y shows a marked protective effect of the Na+/H+ exchange inhibitor HO E 694 in rabbit hearts subjected to 12 hours of hypothermic ischemia a nd strongly suggests that antiport inhibitors could play an effective role in myocardial preservation.