J Mol Cell Cardiol 16, 795 801 (1984) Perfusate Sodium During Ischemia Modifies Post-Ischemic Functional and Metabolic Recovery in the Rabbit Heart* Dale G. Renlund, Gary Gerstenblitht, Edward G. Lakatta, William E. Jacobus, Clayton H. Kallman, and Myron L. Weisfeldt Cardiology Division, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, M D 21205, USA (Received 15 March 1983, acceptedin revised form 28 November 1983) D. G. RENLUND,G. GE~STENBLrrH, E. G. LAKATTA, W. E. JACOBUS, C. H. KALLMAN, AND M. L. WEISFELDT. Perfusate Sodium During Ischemia Modifies Post-Ischemic Functional and Metabolic Recovery in the Rabbit Heart. Journalof Molecular and Cellular Cardiology (1984) 16, 795 801. Metabolic and functional recovery follow- ing 60 minutes of low flow (0.1 ml/min) ischemia were compared in rabbit hearts perfused with normal sodium and potassium, low sodium (120 mM NaC1 replaced by 120 mM LiC1), or zero potassium perfusate during ischemia. During the control, pre-ischemic, and reperfusion periods, all hearts were perfused identically with normal sodium and potassium. 31p NMR was used to monitor intracellular pH (pHi), ATP, and phos- phocreatine (PCr). Developed pressure, end diastolic pressure, phi, and the integrated areas of ATP and PCr were equivalent in the three groups in the pre-ischemic period. The fall in phi, PCr, ATP, and developed pressure and the rise in end diastolic pressure during 60 rain ischemia also did not differ among the three groups. In contrast to the lack of an effect ofperfusate sodium and potassium on the decline in parameters of metabolism and filnction during ischemia, there was a marked difference in the recovery of these indices during reperfusion. Hearts perfused with low sodium during ischemia exhibited the best recovery (expressed as percent of control) of developed pressure (95 + 4%), PCr (106 + 6%), and ATP (51 + 2%) and the smallest rise in end diastolic pressure (229 + 50%) ; hearts perfused with normal sodium and potassium during ischemia had intermediate recovery values for developed pressure (53 _ 10%), PCr (78 + 9%), ATP (45 + 4%) and end diastolic press- ure (487 + 73%) and the hearts perfused with zero potassium solution during ischemia exhibited the poorest recovery of developed pressure (23 + 6%), PCr (49 + 6%), ATP (39 + 5%) and end diastolic pressure (968 + 185%). These results indicate that interventions which do not alter PCr, ATP or pH i during ischemia but which can diminish or enhance intracellular sodium accumulation can respectively improve or impair metabolic and functional recovery during reperfusion. The most likely mechanism to explain these findings is a sodium-dependent calcium influx occurring during reperfusion. This suggests that interventions which lower intracellular sodium or inhibit or reverse the direction of sodium-calcium exchange at the onset of reperfusion may lessen injury following reperfusion ofischemic myocardium. KEY WORDS: Reperfusion of ischemic myocardium; Myocardial energy metabolism; Intracellular pH; Sodium-dependent calcium influx; Ischemia. Introduction Complete functional and metabolic recovery does not occur if the myocardium is reper- fused following 30 to 60 min of severe ischemia [2, 3, 13, 19, 20, 27, 30]. Attempts to improve recovery have been directed towards main- taining intracellular conditions as close to normal as possible during ischemia. Myocard- ial ischemia is accompanied in part by a fall in intracellular pH and high energy phosphates and interventions during ischemia which result in increased intracellular pH and high * This study was supported in part by National Heart, Lung, and Blood Institute Specialized Center of Research Grant No. P-50-HL 17655-08, Bethesda, Maryland and Coronary Heart Disease Research, a program of the American Health Assistance Foundation. Computational assistance was received from CLINFO, sponsored by a grant (5 M01 RR35-20) from the National Institutes of Health. t To whom correspondence should be addressed at: Carnegie 591, The Johns Hopkins Hospital, 600 N. Wolfe Street, Baltimore, MD 21205, USA. 0022 2828/84/090795 + 07 $03.00/0 9 1984 Academic Press Inc. (London) Limited