The possible relationships between intracellular Na+ (Na1+), bioenergetic status and intracellular pH (pH1) in the mechanism for ischemic preconditioning were studied using 23Na and 31P magnetic resonance spectroscopy in isolated Langendorff perfused rat heart. The ischemic preconditioning (three 5-min ischemic episodes followed by two 5-min and one 10-min period of reperfusion) prior to prolonged ischemia (20 min stop-flow) resulted in a decrease in ischemic acidosis and faster and complete recovery of cardiac function (ventricular developed pressure and heart rate) after 30 min of reperfusion. The response of Na1 during ischemia in the preconditioned hearts was characterized by an increase in Na+1 at the end of preconditioning and an accelerated decrease during the first few minutes of reperfusion.
During post-ischemic reperfusion, bioenergetic parameters (PCr/P1 and βATP/P, ratios) were partly recovered without any significant difference between control and preconditioned hearts. The reduced acidosis during prolonged ischemia and the accelerated decrease in Na1+ during reperfusion in the preconditioned hearts suggest activation of Na+/H+ exchanger and other ion transport systems during preconditioning, which may protect the heart from intracellular acidosis during prolonged ischemia, and result in better recovery of mechanical function (LVDP and heart rate) during post-ischemic reperfusion.
BouchardJF, ChouinardJ, LamontagneD.Participation of prostaglandin E2 in the endothelial protective effect of ischaemic preconditioning in isolated rat heart. Cardiovasc Res45(2):418–427, 2000.
6.
WangY, AshrafM.Activation of α1-adrenergic receptor during Ca2+ pre-conditioning elicits strong protection against Ca2+ overload injury via protein kinase C signaling pathway. J Mol Cell Cardiol30(11):2423–2435, 1998.
7.
BabskyA, DolibaNic, DolibaNat, SavchenkoA, WehrliS, OsbakkenM.Na+ effects on mitochondrial respiration and oxidative phosphorylation in diabetic hearts. Exp Biol Med226(6):543–551, 2001.
8.
TaniM, HonmaY, TakayamaM, HasegawaH, ShinmuraK, EbiharaY, TamakiK.Loss of protection by hypoxic preconditioning in aging Fisher 344 rat hearts related to myocardial glycogen content and Na+ imbalance. Cardiovasc Res41:594–602, 1999.
9.
TosakiA, EngelmanDT, EngelmanRM, DasDK. The evolution of diabetic response to ischemia/reperfusion and preconditioning in isolated working rat hearts. Cardiovasc Res31:526–536, 1996.
10.
ImahashiK, NishimuraT, YoshiokaJ, KusuokaH.Role of intracellular Na+ kinetics in preconditioned rat heart. Circ Res88(11):176–182, 2001.
11.
RamasamyR, HongL, AndersonS, LundmarkJ, SchaeferS.Ischemic preconditioning stimulates sodium and proton transport in isolated rat hearts. J Clin Invest96:1464–1472, 1995.
12.
ClarkK, AndersonR, NedelecJ-F, FosterD, AllyA.Intracellular and extracellular spaces and the direct quantification of molar intracellular concentrations of phosphorus metabolites in the isolated rat heart using 31P NMR spectroscopy and phosphate markers. MRM32:181–188, 1994.
13.
SeshanV, BansalN. In vivo 31P and 23Na NMR spectroscopy and imaging. In: Bruch MD, Ed. NMR Spectroscopy Techniques (2nd ed). New York: Marcel Dekker, pp557–607, 1996.
14.
ZhaoP, XiaZF, MalloyCR, SherryAD. TmDOTP5– differentiates two extracellular Na+ signals in hearts perfused with calcium-free buffer. Proc Intl Soc Magn Res Med7:641, 1999.
15.
EngS, MaddafordTG, KardamiE, PierceGN. Protection against myocardial ischemic/reperfusion injury by inhibitors of two separate pathways of Na+ entry. J Mol Cell Cardiol30:829–835, 1998.
16.
GuminaRJ, BuergerE, EickmeierC, MooreJ, DaemmgenJ, GrossG.Inhibition of the Na+/H+ exchanger confers greater cardioprotection against 90 minutes of myocardial ischemia than ischemic preconditioning in dogs. Circulation100:2519–2526, 1999.
17.
MiuraT, OgawaT, SuzukiK, GotoM, ShimamotoK.Infarct size limitation by a new Na+–H+ exchange inhibitor, Hoe 642: difference from preconditioning in the role of protein kinase C. J Am Coll Cardiol29(3):693–701, 1997.
18.
JacobusWE, PoresI, LucasS, WeisfedtM, FlahertyJ.Intracellular acidosis and contractility in the normal and ischemic heart as examined by 31P NMR. J Mol Cell Cardiol14:13–20, 1982.
19.
VandenbergJI, MetcalfeJ, GraceA.Mechanisms of pH1 recovery after global ischemia in the perfused heart. Circ Res72:993–1003, 1993.
20.
GraceAA, KirschelohrHL, MetcalfeJC, SmithGA, WeissbergPI, CragoeEJ, VandenbergJI. Regulation of intracellular pH in the perfused heart by external HCO3– and Na+–H+ exchange. Am J Physiol265:H289–H298, 1993.
21.
CrossHR, RaddaGK, ClarkeK.The role of Na+-K+-ATPase activity during low-flow ischemia in preventing myocardial injury: a 31P, 23Na and 87Rb NMR spectroscopic study. Magn Reson Med34:673–685, 1995
22.
FentonRA, DicksonEW, MeyerTE, DobsonJG. Aging reduces the cardioprotective effect of ischemic preconditioning in the rat heart. J Mol Cell Cardiol32:1371–1375, 2000.
23.
LundmarkJA, TruebloodN, WangLF, RamasamyR, SchaeferS.Repetitive acidosis protects the ischemic heart: implications for mechanisms in preconditioned hearts. J Mol Cell Cardiol31:907–917, 1999.
24.
LiuY, YtrehusK, DowneyJ.Evidence that translocation of protein kinase C is key event during ischemic preconditioning of rabbit myocardium. J Mol Cell Cardiol26:661–668, 1994.
25.
WallertMA, FrohlichO.α1-Adrenergic stimulation of Na+/H+ exchange in cardiac myocytes. Am J Physiol263:C1096–C1102, 1992.
26.
AvkiranM.Protection of the myocardium during ischemia and reperfusion. Na+/H+ exchange inhibition versus ischemic preconditioning. Circulation100:2469–2472, 1999.
27.
RamasamyR, SchaeferS.Inhibition of Na+–H+ exchanger protects diabetic and non-diabetic hearts from ischemic injury: insight into altered susceptibility of diabetic hearts to ischemic injury. J Mol Cell Cardiol31:785–797, 1999.
28.
MenownIBA, AdgeyAAJ. Cardioprotective therapy and sodium-hydrogen inhibition: current concepts and future goals. J Am Coll Cardiol38:1651–1653, 2001.
29.
AvkiranM, MarberMS. Na+\–H+ exchange inhibitors for cardioprotective therapy: progress, problems and prospects. J Am Coll Cardiol39:747–753, 2002.
30.
KuprianovVV, XiangB, ButtlerKW, St-JeanM, DeslauriersR.Energy metabolism, intracellular Na+ and contractile function in isolated pig and rat hearts during cardioplegic ischemia and reperfusion: 23Na and 31P NMR studies. Basic Res Cardiol90:220–233, 1995.
31.
VuorinenK, YilitaloK, PeuhkurinenK, RaatikainenP, Ala-RamiA, HassinenIE. Mechanism of ischemic preconditioning in rat myocardium. Circulation91:2810–2818, 1995.
32.
SchaeferS, CarrLJ, PrusselE, RamasamyR.Effect if glycogen depletion on ischemic injury in isolated rat hearts: insights into preconditioning. Am J Physiol268:H935–H944, 1995.
33.
MurphyE, CrossH, SteenbergenC.Sodium regulation during ischemia versus reperfusion and its role in injury. Circ Res84:1469–1470, 1999.
34.
KohomotoO, BarryW.Mechanism of protective effects of Ca2+ channel blockers on energy deprivation contracture in cultured ventricular myocytes. J Pharmacol Exp Ther248:821–878, 1989.
