Original ArticleNa/H Exchange Inhibition Protects Newborn Heart From Ischemia/Reperfusion Injury by Limiting Na+-dependent Ca2+ OverloadLiu, Hong MD*; Cala, Peter M PhD†; Anderson, Steve E PhD†Author Information From the *Department of Anesthesiology and Pain Medicine; and †Department of Physiology and Membrane Biology, University of California Davis, Davis, CA. Received for publication September 26, 2009; accepted November 9, 2009. Supported by National Institutes of Health grants HL07682, HL56681, HL21179, and by a University of California Davis Health System Research Award. Spectrometers were further supported by NIH RR08206. HOE 694 was a gift from Hoechst Marion Roussel, The Pharmaceutical Company of Hoechst, Germany. The authors report no conflicts of interest. Reprints: Hong Liu, MD, Associate Professor, Department of Anesthesiology and Pain Medicine, University of California Davis Health System, 4150 V Street, Suite 1200, Sacramento, CA 95817 (e-mail: [email protected]). Journal of Cardiovascular Pharmacology: March 2010 - Volume 55 - Issue 3 - p 227-233 doi: 10.1097/FJC.0b013e3181cb599f Buy Metrics Abstract 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. © 2010 Lippincott Williams & Wilkins, Inc.