The results of the Guardian/Expedition trials demonstrate the need for more precisely controlled studies to inhibit Na/H exchange (NHE1) during
ischemia/reperfusion. This is because overwhelming evidence is consistent with the hypothesis that myocardial ischemic injury results in part from increases in intracellular Na (Nai) mediated by NHE1 that in turn promote Na/Ca exchanger-mediated increases in intracellular Ca ([Ca]i) and Ca-dependent cell damage. We used a more potent and specific NHE1 inhibitor
HOE 694 (HOE) to test whether inhibition of NHE1 during
ischemia limits increases in Nai and [Ca]i in newborns. NMR was used to measure pHi, Nai, [Ca]i, and
ATP in isolated newborn rabbit hearts. Perfusion pressure, left ventricular developed pressure, and
creatine kinase were measured. HOE was added before global
ischemia. Results are reported as mean +/- SE. Nai (mEq/kg dry weight) rose from 11.6 +/- 0.9 before
ischemia to 114.0 +/- 16.1 at the end of
ischemia and recovered to 55.2 +/- 11.8 in the control group. During
ischemia and reperfusion, the corresponding values for Nai in the HOE group (63.1 +/- 8.4 and 15.9 +/- 2.5, respectively, P < 0.05) were lower than control. In the control group [Ca]i (nM/L) rose from 331 +/- 41 to 1069 +/- 71 and recovered to 814 +/- 51, whereas in the HOE group [Ca]i rose less (P < 0.05): 359 +/- 50, 607 +/- 85, and 413 +/- 40, respectively. Total
creatine kinase release was significantly reduced in the HOE group. Perfusion pressure and left ventricular developed pressure also recovered significantly better in the HOE group than in the control. In conclusion, NHE1 inhibition diminishes
ischemia-induced increases in Nai and therefore [Ca], and thus diminishes myocardial injury in neonatal hearts.