Sodium regulation during ischemia versus reperfusion and its role in injury.

Abstract

HomeCirculation ResearchVol. 84, No. 12Sodium Regulation During Ischemia Versus Reperfusion and Its Role in Injury Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBSodium Regulation During Ischemia Versus Reperfusion and Its Role in Injury Elizabeth Murphy, Heather Cross and Charles Steenbergen Elizabeth MurphyElizabeth Murphy From the National Institute of Environmental Health Sciences, Research Triangle Park, NC; and Department of Pathology, Duke University Medical Center, Durham, NC. Search for more papers by this author , Heather CrossHeather Cross From the National Institute of Environmental Health Sciences, Research Triangle Park, NC; and Department of Pathology, Duke University Medical Center, Durham, NC. Search for more papers by this author and Charles SteenbergenCharles Steenbergen From the National Institute of Environmental Health Sciences, Research Triangle Park, NC; and Department of Pathology, Duke University Medical Center, Durham, NC. Search for more papers by this author Originally published25 Jun 1999https://doi.org/10.1161/01.RES.84.12.1469Circulation Research. 1999;84:1469–1470There are considerable data to support the general hypothesis that accumulation of [Na+]i during ischemia and early reperfusion leads, via Na+/Ca2+ exchange, to elevated [Ca2+]i, resulting in myocardial damage.12345678910 Despite the strong support for the general aspects of this hypothesis, there is controversy regarding some details that have important implications for the design of therapeutic interventions. The relative importance of the increase in [Na+]i during ischemia versus the increase in [Na+]i during reperfusion in contributing to the rise in [Ca2+]i and resultant injury is debated. These issues are important because it has been suggested that inhibition of the Na+/H+ exchanger (NHE) during reperfusion alone would be beneficial. This would allow clinical intervention after an ischemic episode. It is also important to understand why an increase in [Na+]i is detrimental. It is commonly assumed that [Na+]i is detrimental because it leads to increased [Ca2+]i during reperfusion, either due to diminished Ca2+ efflux via Na+/Ca2+ exchange or due to increased Ca2+ influx due to reverse Na+/Ca2+ exchange. Recent data presented by Cross et al9 suggest that reverse Na+/Ca2+ exchange is involved in postischemic contractile dysfunction. However, an increase in [Na+]i could also be detrimental because of effects on K+ loss11 or energetics. An understanding of the mechanism responsible for the detrimental effects of Na+ accumulation is important for the design of therapeutic interventions. A study12 published in this issue of Circulation Research adds new insight into these important issues.What Is the Relative Contribution of Na+ Entry During Ischemia Versus Reflow?Lazdunski et al1 originally hypothesized that during ischemia, protons will accumulate in the cell and in the extracellular space, and the low pHo would inhibit NHE. On reperfusion, restoration of normal pHo would stimulate NHE, leading to a rapid increase in [Na+]i, which would in turn stimulate Na+/Ca2+ exchange, leading to [Ca2+]i overload. If this hypothesis is correct, addition of NHE inhibitors at the start of reflow should reduce [Ca2+]i overload and be protective. However, there are conflicting data regarding the protective effects of NHE inhibitors. NHE inhibitors are protective if administered before or during ischemia; however when NHE inhibitors are administered at the start of reperfusion, there are data suggesting protection, partial protection, and no protection (see Murphy et al10 and references within). In perfused heart models, measurements of pHi, [Na+]i, and [Ca2+]i during ischemia and reflow have shown a rise in [Na+]i and [Ca2+]i during ischemia.3568 The original model of Lazdunski et al1 assumed that NHE would not contribute much to the rise in [Na+]i during ischemia because of the low pHo.1 Although low pHo reduces activity of NHE, Vaughan-Jones et al13 have shown that NHE can still operate. It is also suggested that other mechanisms such as the noninactivating Na+ channels contribute to the rise in [Na+]i during ischemia.14 The mechanism responsible for the rise in [Na+]i is debated,1014 but it is likely that both Na+/H+ exchange and noninactivating Na+ channels contribute. Imahashi et al12 show that the amount of [Na+]i that exchanges with [Ca2+]o is dependent on the amount of [Na+]i accumulated during ischemia, as well as the relative rates at which [Na+]i is extruded via Na+/Ca2+ exchange relative to other Na+ extrusion mechanisms. In agreement with other investigators, Imahashi et al12 clearly demonstrate that accumulation of [Na+]i during ischemia is an important source of the [Na+]i that exchanges with Ca2+ on reperfusion.Lazdunski et al1 hypothesized that activation of Na+/H+ exchange on reflow would lead to an increase in [Na+]i, which would lead to reversed Na+/Ca2+ exchange. Interestingly, most investigators6810 including Imahashi et al12 report a decline in [Na+]i on reperfusion. Imahashi et al acknowledged in their discussion that although NHE “produced massive Na+ influx to remove H+ during ischemic acidosis, this inhibition did not significantly alter [Na+]i kinetics during reperfusion” (page 1405). They speculate that Na+ influx via NHE during reperfusion is markedly smaller than Na+ efflux pathways. An important finding of Imahashi et al is that Na+ efflux via Na+/Ca2+ exchange is a major Na+ efflux pathway during reperfusion. Van Emous et al15 have shown the importance of the Na+-K+ ATPase to Na+ efflux during reperfusion. They reported that inhibition of the Na+-K+ ATPase unmasks the increase in [Na+]i that occurs on reperfusion by showing that in the presence of ouabain there is an increase in Na+ on reperfusion. They also showed that the increase in Na+ is lower in the presence of EIPA, implying that NHE is active during early reperfusion. Imahashi et al12 also conclude that their data, which show that inhibition of Na+/H+ exchange during reperfusion does not alter Na+ efflux kinetics, are “inconsistent with the hypothesis that Na+ entry via Na+/H+ exchange just after reperfusion is a critical trigger for reperfusion injury” (page 1405). This point may require additional study. Although the data are convincing that Na+ entry during ischemia is a major regulator of ionic changes during early reperfusion, it is difficult to exclude a role for Na+ entry during the first few seconds of reperfusion. It is likely that, depending on the experimental model, Na+ entry via Na+/H+ exchange on reperfusion will contribute to Ca2+ entry and [Ca2+]i overload. Studies by Tani and Neely,3 who measured calcium uptake using 45Ca2+, have shown that inhibitors of Na+/H+ exchange given only at reperfusion attenuate 45Ca2+ uptake on reflow; the reduction in 45Ca2+ uptake was greater when amiloride was added during ischemia and reperfusion, but there was a slight (but not significant) attenuation of 45Ca2+ uptake when amiloride was added only at reflow. It is likely that some of the Na+ that enters via Na+/H+ exchange at the start of reperfusion will exchange with Ca2+ and contribute to [Ca2+]i overload. Furthermore, the first few seconds of reperfusion are most important for Na+ entry via NHE, and it is possible that when EIPA is added at the start of reperfusion, it does not reach the myocytes soon enough to be effective. This might account for the lack of effect of EIPA on the rate of Na+ efflux.Taken together, the data in the literature and the data of Imahashi et al12 suggest that the accumulation of [Na+]i during ischemia accounts for a large proportion of the [Na+]i that exchanges with Ca2+ on reperfusion. However, Na+ entry via NHE during the first seconds of reperfusion may also be important. Regardless of the proportion of [Na+]i that enters during ischemia versus reperfusion, an elegant series of studies27 have shown that manipulations that attenuate Na+/Ca2+ exchange at the start of reperfusion such as lowering perfusate Ca2+, raising [Na+]o, or acid reperfusion all reduce postischemic contractile dysfunction. Data presented by Imahashi et al12 enhance these earlier studies by showing that low Ca2+ reperfusion reduces the rate of Na+ efflux, consistent with inhibition of Na+/Ca2+ exchange, providing support for the conclusion that inhibition of Na+/Ca2+ exchange during reperfusion is beneficial.Why Is an Increase in [Na+]i Detrimental?Imahashi et al12 demonstrate that it is the elevated [Na+]i at the start of reperfusion, which exchanges with Ca2+, that is responsible for postischemic contractile dysfunction. They show that hearts that have nearly identical [Na+]i levels at the end of ischemia have differences in postischemic contractile dysfunction, which correlate with differences in the rate of Na+/Ca2+ exchange during reperfusion. The data show that slowing Na+ extrusion, by reducing [Ca2+]o, improves postischemic function, and that enhancing Na+ extrusion by elevating [Ca2+]o worsens postischemic contractile function. In addition, perfusion with a Na+/Ca2+ exchange inhibitor reduces the rate of Na+ extrusion and improves postischemic contractile function. The data presented by Imahashi et al12 clearly show that it is not the amount of [Na+]i accumulated during ischemia or reperfusion that results in postischemic contractile dysfunction; rather, it is the amount of [Na+]i that exchanges with Ca2+ that influences recovery of function. These data combined with data in the literature suggest that inhibition of Na+/Ca2+ exchange on reperfusion may be a promising therapeutic target.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Elizabeth Murphy, 111 Alexander Dr, Room E216, Mail drop D2-03, Box 12233, NIEHS, Research Triangle Park, NC 27707. E-mail [email protected] References 1 Lazdunski M, Frelin C, Vigne P. The sodium/hydrogen exchange system in cardiac cells: its biochemical and pharmacological properties and its role in regulating internal concentrations of sodium and internal pH. J Mol Cell Cardiol.1985; 17:1029–1042.CrossrefMedlineGoogle Scholar2 Kusuoka H, Porterfield JK, Weisman HF, Weisfelt ML, Marbán E. Pathophysiology and pathogenesis of stunned myocardium: depressed Ca2+ activation of contraction as a consequence of reperfusion-induced cellular calcium overload in ferret hearts. J Clin Invest.1987; 79:950–961.CrossrefMedlineGoogle Scholar3 Tani M, Neely J. Role of intracellular Na+ and Ca2+ overload and depressed recovery of ventricular function of reperfused ischemic rat hearts: possible involvement of H+-Na+ and Na+-Ca2+ exchange. Circ Res.1989; 65:1045–1056.CrossrefMedlineGoogle Scholar4 Karmazyn M. Amiloride enhances postischemic ventricular recovery: possible role of the Na-H exchange. Am J Physiol.1988; 255:H608–H615.MedlineGoogle Scholar5 Murphy E, Perlman M, London RE, Steenbergen C. Amiloride delays the ischemia-induced rise in cytosolic free calcium. Circ Res.1991; 68:1250–1258.CrossrefMedlineGoogle Scholar6 Pike MM, Luo CS, Clark MD, Kirk KA, Kitakaze M, Madden MC, Cragoe EJ, Pohost GM. NMR measurements of Na+ and cellular energy in ischemic rat heart: role of Na+-H+ exchange. Am J Physiol.1993; 265:H2017–H2026.MedlineGoogle Scholar7 Kusuoka H, Camilion de Hurtado MC, Marbán E. Role of sodium/calcium exchange in the mechanism of myocardial stunning: protective effect of reperfusion with high sodium. J Am Coll Cardiol.1993; 21:240–248.CrossrefMedlineGoogle Scholar8 Liu H, Cala PM Anderson SE. Ethylisopropylamiloride diminishes changes in intracellular Na, Ca and pH in ischemic newborn myocardium. J Mol Cell Cardiol.1997; 29:2077–2086.CrossrefMedlineGoogle Scholar9 Cross HR, Lu L, Steenbergen C, Philipson KD, Murphy E. Overexpression of the cardiac Na+/Ca2+ exchanger increases susceptibility to ischemia/reperfusion injury in male, but not female, transgenic mice. Circ Res.1998; 83:1215–1223.CrossrefMedlineGoogle Scholar10 Murphy E, Cross HR, Steenbergen C. Na+/H+ and Na+/Ca2+ exchange: their role in the rise in cytosolic free [Ca2+] during ischemia and reperfusion. Eur Heart J Suppl. In press.Google Scholar11 Shivkumar K, Deutsch NA, Lamp ST, Khuu K, Goldhaber JI, Weiss JN. Mechanism of hypoxic K loss in rabbit ventricle. J Clin Invest.1997; 100:1782–1788.CrossrefMedlineGoogle Scholar12 Imahashi K, Kusuoka H, Hashimoto K, Yoshioka J, Yamaguchi H, Nishimura T. Intracellular sodium accumulation during ischemia as the substrate for reperfusion injury. Circ Res.1999; 84:1401–1406.CrossrefMedlineGoogle Scholar13 Vaughan-Jones RD, Wu M-L. Extracellular H+ inactivation of Na+-H+ exchange in the sheep Purkinje fibre. 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Li Q, Cui N, Du Y, Ma H, Zhang Y and Schlossmann J (2013) Anandamide Reduces Intracellular Ca2+ Concentration through Suppression of Na+/Ca2+ Exchanger Current in Rat Cardiac Myocytes, PLoS ONE, 10.1371/journal.pone.0063386, 8:5, (e63386) Shoshan-Barmatz V, De S and Meir A (2017) The Mitochondrial Voltage-Dependent Anion Channel 1, Ca2+ Transport, Apoptosis, and Their Regulation, Frontiers in Oncology, 10.3389/fonc.2017.00060, 7 June 25, 1999Vol 84, Issue 12 Advertisement Article InformationMetrics © 1999 American Heart Association, Inc.https://doi.org/10.1161/01.RES.84.12.1469 Originally publishedJune 25, 1999 KeywordsNa+/Ca2+ exchangeNa+/H+ exchangeCa2+ overloadstunningPDF download Advertisement