This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Karmazyn, M. Articles by Kusumoto, K. Search for Related Content PubMed PubMed Citation Articles by Karmazyn, M. Articles by Kusumoto, K. Related Collections Ischemic biology - basic studies Ion channels/membrane transport

(Circulation Research. 1999;85:777-786.)
© 1999 American Heart Association, Inc.

Reviews

The Myocardial Na⁺-H⁺ Exchange

Structure, Regulation, and Its Role in Heart Disease

Morris Karmazyn, Xiaohong Tracey Gan, Rachael A Humphreys, Hiroyuki Yoshida, Keiji Kusumoto

From the Department of Pharmacology and Toxicology, University of Western Ontario, London, Ontario, Canada.

Correspondence to Dr Morris Karmazyn, Department of Pharmacology and Toxicology, Medical Sciences Bldg, University of Western Ontario, London, Ontario N6A 5C1, Canada. E-mail mkarm{at}julian.uwo.ca

	Abstract

Top Abstract Introduction NHE1 Structure and Cellular... Regulation of NHE1 Activity Transcriptional Regulation of... NHE1 in the Ischemic... NHE and Other Cardiac... Conclusions References

 
Abstract—The Na⁺-H⁺ exchange (NHE) is a major mechanism by which the heart adapts to intracellular acidosis during ischemia and recovers from the acidosis after reperfusion. There are at least 6 NHE isoforms thus far identified with the NHE1 subtype representing the major one found in the mammalian myocardium. This 110-kDa glycoprotein extrudes protons concomitantly with Na⁺ influx in a 1:1 stoichiometric relationship rendering the process electroneutral, and its activity is regulated by numerous factors, including phosphorylation-dependent processes. There is convincing evidence that NHE mediates tissue injury during ischemia and reperfusion, which probably reflects the fact that under conditions of tissue stress, including ischemia, Na⁺-K⁺ ATPase is inhibited, thereby limiting Na⁺ extrusion, resulting in an elevation in [Na⁺]_i. The latter effect, in turn, will increase [Ca²⁺]_i via Na⁺-Ca²⁺ exchange. In addition, NHE1 mRNA expression is elevated in response to injury, which may further contribute to the deleterious consequence of pathological insult. Extensive studies using NHE inhibitors have consistently shown protective effects against ischemic and reperfusion injury in a large variety of experimental models and has led to clinical evaluation of NHE inhibition in patients with coronary artery disease. Emerging evidence also implicates NHE1 in other cardiac disease states, and the exchanger may be particularly critical to postinfarction remodeling responses resulting in development of hypertrophy and heart failure.

Key Words: Na⁺-H⁺ exchange • ischemia/reperfusion • remodeling • hypertrophy • heart failure

	Introduction

Top Abstract Introduction NHE1 Structure and Cellular... Regulation of NHE1 Activity Transcriptional Regulation of... NHE1 in the Ischemic... NHE and Other Cardiac... Conclusions References

 
Intracellular pH regulation in the cardiac myocyte is dependent on 4 primary membrane transporters, which are Na⁺-H⁺ exchange (NHE) and Na⁺-HCO₃^- symport, both of which are activated after acid loading and mediate acid efflux, as well as a Cl^--HCO₃^- and Cl^--OH^- exchanger, which are stimulated by intracellular alkalosis and are involved in proton influx.¹ NHE plays a pivotal role in the regulation of pH_i by removing protons that are continuously generated under normal cellular homeostatic processes, as well as during ischemia. NHE1, the so-called housekeeping isoform is ubiquitously distributed in most tissues and is the primary NHE subtype found in the mammalian cardiac cell.^{2 3 4} There are at present 5 known NHE isoforms found in the plasma membrane in mammalian cells.^{2 3 4} A yeast NHE homologue that is intracellularly localized has been identified. Although initially proposed as a mitochondrial NHE in various tissues including heart,⁵ recently endosomal localization has been proposed.⁶ Cardiac cells lack NHE2 to NHE5 isoforms, although, under prolonged (12-hour) autoradiographic exposure, very faint levels of NHE3 mRNA were detected in rat heart.⁷ The function of NHE, or at least isoforms NHE1 to NHE5, is the regulation of pH_i and cell volume through extrusion of protons in exchange for sodium influx in a 1:1 stoichiometric relationship rendering the process electroneutral.⁸ Although NHE is a major regulator of pH_i, it shares this function with a number of other cellular homeostatic pH regulatory systems, as referred to above. Whereas the localization of the other NHE isoforms appears to be restricted to the plasma membrane, the possibility that NHE6 is a mitochondrial isoform suggests that this subtype may regulate mitochondrial function particularly with respect to intramitochondrial Na⁺ and H⁺ levels.⁵ Because mitochondrial calcium levels can be regulated by Na⁺ and H⁺ gradients, NHE6 could represent an important modulator of mitochondrial calcium, particularly under pathological conditions.

Individual NHE isoforms represent distinct gene products and differ by tissue distribution, molecular structures, sensitivities to pharmacological inhibitors, and isoform-dependent distinct roles in cell regulation. Although NHE6 shares only a 20% amino acid similarity compared with the other currently known NHE isoforms found in the plasma membrane, amino acid identity between these (NHE1 to NHE5) subtypes is markedly greater, ranging from 34% to 60%. Different sensitivities of NHE isoforms to pharmacological inhibition represents a rather fortuitous characteristic that has aided in the development of therapeutic agents, such as newly developed NHE1-specific inhibitors including 4-isopropyl-3-methylsulphonylbenzoyl-guanidine methanesulphonate (HOE 642) (cariporide) or 2-methyl-5-methylsulphonyl-l-(1-pyrrollyl)-benzoyl-guanidine (EMD 85131) (see below). This review will focus primarily on NHE1, which has a major role in the regulation of cardiac function, particularly under pathological conditions and, as discussed below, is emerging as a potential downstream mediator in complex cell signaling, especially in response to receptor activation by a variety of endobiotics. A number of more general overviews of NHE can be recommended.^{2 3 4}

	NHE1 Structure and Cellular Localization

Top Abstract Introduction NHE1 Structure and Cellular... Regulation of NHE1 Activity Transcriptional Regulation of... NHE1 in the Ischemic... NHE and Other Cardiac... Conclusions References

 
Figure 1 represents the putative topological model for the mammalian NHE1, which consists of the following 2 principal domains: a 500–amino acid transmembrane domain and a 315–amino acid highly hydrophilic carboxyl-terminus cytoplasmic domain. The number of membrane-spanning units differs according to NHE isoform type, although NHE1 contains 12 such spanning regions that are critical for the maintenance of NHE1 function in terms of proton extrusion. The hydrophilic cytoplasmic region plays an important role in modulation of the exchanger, especially through phosphorylation-dependent reactions.⁹ This region is NHE isoform specific, which likely accounts for differential regulation by diverse factors or stimuli.^{10 11} Although the predicted molecular mass of NHE1 is 91 kDa, because the protein is glycosylated its apparent molecular mass is 110 kDa.

View larger version (66K): [in this window] [in a new window]   Figure 1. Putative topological model of 815–amino acid NHE1 showing 12 transmembrane-spanning segments and hydrophilic carboxyl terminus, with indications of proposed regulatory sites. Localization of the putative H+ sensor that accounts for the sensitivity of NHE to pHi has not been confirmed but likely resides in the lipophilic terminus transmembrane region. Refer to text for details.

It has recently been suggested that NHE1 is localized primarily in the intercalated disk region of atrial and ventricular myocytes in close proximity to connexin 43, and, to a lesser degree, at the transverse tubular systems.¹² Such localization of NHE1 may implicate the antiporter in cell-to-cell ion-dependent communication via gap junctions, as well as the regulation of [Ca²⁺]_i levels through proton-dependent modulation of Ca²⁺ channels in transverse tubules. It is not known whether the apparent specialized localization of NHE1 in the normal cardiomyocyte is preserved when hearts are subjected to pathological factors such as ischemia.

	Regulation of NHE1 Activity

Top Abstract Introduction NHE1 Structure and Cellular... Regulation of NHE1 Activity Transcriptional Regulation of... NHE1 in the Ischemic... NHE and Other Cardiac... Conclusions References

 
Intracellular acidosis is a major stimulus for NHE1 activation.¹³ Although Na⁺ can also affect NHE1, it is unlikely to be a major regulator within a physiological range (7 to 16 mmol/L) of [Na⁺]_i.¹³ Approximately 60% of proton removal capability of the cardiac cell is accomplished via NHE.¹⁴ NHE1 is regulated by hormones, paracrine/autocrine regulators, and mechanical stimuli such as hyperosmotic challenge,¹⁵ mostly via phosphorylation reactions (reviewed in Reference 16¹⁶ ), resulting in increased affinity of the so-called H⁺ sensor (Figure 1). Although the nature of this sensor, which accounts for the exquisite sensitivity of NHE1 to changes in pH_i, is poorly understood, there is evidence (reviewed in Reference 17¹⁷ ) that proton binding triggers a protein conformational change within an NHE oligomer resulting in NHE activation. The sensitivity of the H⁺ sensor is greatly regulated by distinct regions of the C-terminal, and agonists that activate NHE1 via phosphorylation reactions shift the pH_i-NHE1 curve toward the alkaline range, that is, there is greater activity at less acidic pH_i. Studies using C-terminal deletion constructs have demonstrated that when the C terminus beyond position 698 is deleted, the serum-stimulated phosphorylation was no longer observed, whereas with elimination of the C terminus beyond position 635, constitutive phosphorylation was abolished.¹⁸

As summarized in Figure 2, various signaling pathways can stimulate cardiac NHE1. These represent modulators of cardiac activity as well as potential contributors to cardiac pathology, including endothelin-1,^{19 20 21 22} angiotensin II,^{23 24 25} ₁-adrenergic agonists,^{26 27 28} thrombin,²⁹ and growth factors.^{17 30} In addition, cardiotoxic ischemic metabolites, such as hydrogen peroxide³¹ and lysophosphatidylcholine,³² stimulate NHE1 activity. The effects of these agonists generally reflect the stimulation of phosphoinositide hydrolysis and subsequent activation of kinases such as protein kinase C (PKC), which then phosphorylate and activate NHE1.^{2 15 33}

View larger version (75K): [in this window] [in a new window]   Figure 2. Simplified illustration of possible pathways leading to NHE activation and potential relevance to cell growth. Briefly, activation of NHE can occur via a phospholipase C (PLC) stimulation phosphoinositide (PI) hydrolysis, leading to PKC activation in response to receptor activation. In addition, stimulation of the MAP kinase (MAPK and MAPKK) system through growth factors (GF), cytokines, and H2O2 further stimulates NHE activity, as can ischemic metabolites including lysophosphatidylcholine (LPC) and H+. Various concomitant processes, including an inositol trisphosphate (IP3)–induced release of [Ca2+]i, cellular alkalinization via NHE, or MAP kinase modulation of nuclear transcriptional factors, can affect protein synthesis and increase cell growth. The increased [Ca2+]i can potentially also increase NHE activity via reversing of the autoinhibitory state of the antiporter via a calmodulin (CaM)–dependent process. The figure also shows that depletion of intracellular ATP levels may have an inhibitory effect on NHE activity. Refer to text for further description. DAG indicates diacylglycerol; PIP2, phosphatidylinositol 4,5-biphosphate; Gq, Gq subtype GTP-binding protein; and R, GF receptor.

NHE1 has consensus sequences for mitogen-activated protein (MAP) kinase, and the enzyme has been implicated in NHE1 phosphorylation and activation.^{31 34} In skeletal muscle, phosphorylation occurs in the 178 amino acids of the C terminus, although removal of this residue still resulted in 50% growth factor activation of the exchanger.³⁴ Recently, a role for p90rsk in MAP kinase-dependent phosphorylation of NHE1 has been demonstrated using rat myocardium.³⁵ MAP kinase–dependent regulation of NHE1 may be important in cardiac disease, as stimulation of the Ras/MAP kinase pathway by cytokines or growth factors may contribute to a participatory role of NHE1 in long-term adaptive responses (see below). Moreover, this system is stimulated by hypoxia, which may contribute to NHE1 activation.³⁶

NHE1 activity can also be regulated by phosphorylation-independent mechanisms.^{16 17 30 37} For example, complete removal of sites that are phosphorylated in response to thrombin/insulin does not abolish NHE1 activity. Conversely, NHE1 activity can be completely eliminated by deletion of positions 567 and 635, which still preserves mitogen-stimulated phosphorylation.³⁷ There appear to be a number of important regulators of NHE1 that act through such phosphorylation-independent mechanisms. For example, both high- and low-affinity calmodulin binding sites on the C-terminal domain of NHE1 have been identified as resulting in NHE activation and are thought to represent a reversal of the autoinhibitory state of the antiporter that exists under unstimulated conditions.^{37 38 39} If this occurs in the heart, it may suggest an alternate mechanism for NHE1 activation under pathological conditions when [Ca²⁺]_i levels are elevated.

ATP may also regulate NHE1, given that cytoplasmic ATP depletion leads to reduced transport activity^{39 40} independently of phosphorylation and even with truncated NHE1 mutants lacking phosphorylation sites.⁴¹ A yet-to-be-identified cofactor may mediate the effect of ATP depletion on NHE1 activity, possibly as a consequence of the inability of this cofactor to interact with NHE1 under conditions of low ATP levels.^{41 42} Although speculative, it is possible that very low ATP levels in the ischemic myocytes counter the stimulatory effect of intracellular acidosis on NHE1 activity.

In noncardiac tissue, a number of G proteins, including G_q, G₁₂, and G₁₃, can modulate NHE activity.^{43 44 45 46} The mechanisms for G protein–induced stimulation appear to be very complex and heavily dependent on G protein type. For example, G₁₂ and G_q have been shown to activate NHE1 via a PKC-dependent mechanism, whereas the effect of G₁₃ is most likely PKC independent.⁴³ It appears that G₁₃ utilizes a distinct kinase cascade using the Rho family of GTPases (Cdc42 and RhoA) to activate NHE1 through MAP/extracellular signal–regulated kinase kinase 1 (MEKK1)–dependent (Cdc42) and –independent (RhoA) pathways.⁴⁶

	Transcriptional Regulation of NHE1

Top Abstract Introduction NHE1 Structure and Cellular... Regulation of NHE1 Activity Transcriptional Regulation of... NHE1 in the Ischemic... NHE and Other Cardiac... Conclusions References

 
There have been relatively few studies dealing with regulation of expression of the antiporter. Such research has become fruitful after the initial cloning of the promoter region of the NHE1 gene from several species. Kolyada et al⁴⁷ utilized footprinting analysis to identify the existence of 4 protected sites that were able to bind hepatic proteins. Two of these binding regions (B and C) contain the binding site for activator protein-2 (AP-2) or an AP-2–like transcription factor.⁴⁸ Although this site contributes to the transcriptional regulation of NHE1 in cardiomyocytes, it appears that 75% of the NHE1 promoter activity in these cells is due to elements distal to the AP-2 site.⁴⁹ Another element consisting of 15- to 20-dT residues, which a may play a role in promoter regulation in various cell types, has been characterized,⁵⁰ although transcriptional regulation in the cardiac cell remains to be determined.

	NHE1 in the Ischemic and Reperfused Myocardium

Top Abstract Introduction NHE1 Structure and Cellular... Regulation of NHE1 Activity Transcriptional Regulation of... NHE1 in the Ischemic... NHE and Other Cardiac... Conclusions References

 
NHE1 Activity in Ischemia and Reperfusion
Undoubtedly, the most widely studied area in terms of the role of NHE in cardiac pathology pertains to its role in the ischemic and reperfused myocardium. Ischemia-induced acidosis represents a major stimulus for NHE activation with further stimulation by ischemic metabolites such as hydrogen peroxide and lysophosphatidylcholine, as well as paracrine and autocrine factors acting through phosphorylation-dependent processes.

NHE1 mRNA Expression in Ischemia and Reperfusion
In addition to activity, NHE1 mRNA levels are also increased in both the ischemic myocardium as well as in hearts exposed to cardiotoxic ischemic metabolites,^{51 52} including hydrogen peroxide and lysophosphatidylcholine,⁵² suggesting that cardiac insult increases NHE1 expression. In contrast, it is interesting that ischemic preconditioning reduces NHE1 mRNA levels and prevents the ability of either ischemia or chemical cardiotoxic agents to increase expression.⁵²

Stimulation of NHE1 mRNA expression is also observed in left ventricular myocardium after coronary artery ligation with or without reperfusion, which interestingly does not occur in animals treated with the NHE1 inhibitor cariporide.⁵³ The basis for the latter is not known; however, because cariporide did not affect basal NHE1 mRNA levels, it is possible that it reflects an inhibition of secondary components, produced by the ischemic myocardium, which have the ability to stimulate NHE1 expression. For example, by reducing cell injury and the resultant production of ischemic metabolites such as hydrogen peroxide and lysophosphatidylcholine, the potential stimuli for increased NHE1 expression would be reduced.

Mechanistic Basis for NHE Involvement in Myocardial Ischemic and Reperfusion Injury
General Concepts
Because NHE activation is associated with Na⁺ influx, the exchanger may also regulate [Na⁺]_i under some conditions. Indeed, activation of the NHE in the cardiac myocyte accounts for up to 50% of the basal membrane permeability to Na⁺,⁵⁴ which may explain the mechanistic basis for the ability of amiloride to decrease the cardiac effects of digitalis glycosides.^{55 56}

Increasing [Na⁺]_i will also affect [Ca²⁺]_i levels in the cardiac cell that will affect cardiac function, especially under ischemia and reperfusion. As illustrated in Figure 3, the basis for NHE involvement in myocardial ischemic and reperfusion injury reflects a close interaction between ion-regulatory processes found in the cardiac cell, especially NHE, Na⁺-Ca²⁺ exchange, and the Na⁺-K⁺ ATPase; indeed, inhibition of the latter during ischemia is an important prerequisite for NHE involvement in ischemic and reperfusion injury and forms the basis for a Na⁺-dependent elevation in [Ca²⁺]_i levels resulting in cell injury. It is known that changes in pH_i and in cytosolic Ca²⁺ levels are closely related,^{57 58} most likely because Na⁺ entering via NHE activation is exchanged for Ca²⁺ via Na⁺-Ca²⁺ exchange, leading to an increase in [Ca²⁺]_i, a concept supported by various studies.^{57 59 60 61} For example, amiloride attenuated the ability of ouabain to elevate [Na⁺]_i and to increase the rate and extent of Ca²⁺ entry through the Na⁺-Ca²⁺ exchange.⁵⁴ As amiloride on its own did not markedly alter [Na⁺]_i, it was reasoned that a balance must exist between the rate of Na⁺ entry via NHE and the rate of Na⁺ efflux via the Na⁺-K⁺ ATPase.⁵⁴ Other investigators measured total cell Ca²⁺ during and after an NH₄⁺-induced acid loading in chick heart muscle cells.⁶² During exposure to NH₄⁺, [Ca²⁺]_i declined by 30%, whereas changing to a NH₄⁺-free solution, which results in intracellular acidification and stimulation of the NHE, produced an increase in [Ca²⁺]_i back to control values. The net uptake of Ca²⁺ and net Na⁺ extrusion were temporally correlated, leading the authors to suggest that both the Na⁺-Ca²⁺ exchange and the Na⁺-K⁺ ATPase were important in re-establishing the Na⁺ gradient subsequent to pH_i regulation. Duan and Moffat⁶³ have previously demonstrated that accumulation of [Ca²⁺]_i by isolated ventricular myocytes during realkalinization after a brief period of lactate acidosis was inhibited by hexamethylene amiloride in a concentration-dependent fashion, although this was completely dependent on cell stimulation and did not occur in quiescent cells during the initial 4 minutes of realkalinization.⁶³ This observation suggested that the Na⁺-K⁺ ATPase by itself was able to dissipate the acidosis-induced Na⁺ load in the absence of Na⁺ entry through the voltage-dependent channels. This represents an important difference in the cellular response to NHE activation under normoxic versus ischemic conditions in that in the latter Na⁺-K⁺ ATPase inhibition would preclude an effective removal of Na⁺ ions, thereby causing Ca²⁺ overloading conditions. Indeed, ouabain enhances injury in reoxygenated myocytes, as evidenced by enhanced cytosolic Ca²⁺ oscillations, which is attenuated by NHE inhibition.⁶⁴

View larger version (109K): [in this window] [in a new window]   Figure 3. Illustration demonstrating the interrelationships between ion-regulatory transporters as a mechanism for NHE involvement in cardiac injury in the ischemic and reperfused myocardium. Activation of the exchanger occurs as a consequence of various intracellular and extracellular factors but most importantly as a result of intracellular acidosis. The increased influx of Na+ cannot be removed efficiently because of inhibition of Na+-K+ ATPase. As a result, [Na+]i levels will increase, producing elevations in [Ca2+]i levels via Na+-Ca2+ exchange (NCE). Refer to text for detailed explanation.

NHE Activation During Reperfusion
It has been proposed⁵⁷ that activation of the NHE at the time of reflow represents a major component of reperfusion-associated dysfunction and cell injury. This would contribute to restoration of pH_i; however, on the basis of the concepts discussed in the preceding section, the concomitant Na⁺ influx would increase [Ca²⁺]_i through the Na⁺-Ca²⁺ exchanger. Na⁺-Ca²⁺ exchange involvement in ischemia and reperfusion injury has recently been reinforced by the finding that such injury is enhanced in hearts of mice overexpressing this exchanger, although, interestingly, the phenomenon was not observed in female animals.⁶⁵ The fact that injury was exacerbated in animals that overexpress Na⁺-Ca²⁺ exchange could also be taken to suggest that this exchanger actively participates in injury possibly by increasing Ca²⁺ influx through a reverse mode process.

An alternate concept regarding a reperfusion-induced NHE-dependent injury through Ca²⁺-independent mechanisms has also been proposed. This hypothesis, termed the pH paradox, suggests that during ischemia, the loss in intracellular ATP results in phospholipase and protease activation, which results in cell membrane injury; however, because these enzymes possess pH optima in the alkaline range, their detrimental effects are attenuated by ischemia-induced acidosis. However, on reperfusion the rapid restoration of pH_i reverses the suppression of proteases and other enzymes seen during the ischemic period and results in cell death.⁶⁶ In addition, the restoration of pH_i stimulates the formation of the mitochondrial membrane permeability transition, which results in depression of ATP resynthesis via oxidative phosphorylation pathways.⁶⁶ The relative contribution of this process to NHE-dependent cardiac injury is, however, not certain, but is supported by myocyte studies illustrating a protective effect of NHE inhibition against reoxygenation that can be dissociated from [Ca²⁺]_i levels.⁶⁷ It should be noted that the concept of the pH paradox involves almost totally reperfusion injury per se and therefore fails to account for the potential importance of NHE inhibition during ischemia as a cardioprotective approach, as will be discussed in the following section.

NHE Activation During Ischemia
There is substantial evidence that activation of the antiporter during ischemia per se is of major importance in mediating cardiac injury. Indeed, the conditions necessary for NHE activation are present in the ischemic myocardium, including intracellular acidosis, Na⁺-K⁺ ATPase inhibition, and the increased production of intracellular ischemic metabolites as well as hormonal, paracrine, and autocrine factors that activate NHE without the necessity of reperfusion. A close association between Na⁺ and Ca²⁺ accumulation in the ischemic nonreperfused myocardium and the ability of NHE inhibitors to attenuate these changes has been reported.⁶⁸ Moreover, as discussed in greater detail below, the salutary effects of NHE inhibitors are markedly more pronounced when the drug is present during the ischemic period compared with addition before reperfusion.

There is still uncertainty as to whether inhibiting NHE during ischemia accentuates intracellular acidosis. For example, one study using ³¹P nuclear magnetic resonance spectroscopy showed that the NHE inhibitor dimethylamiloride resulted in greater acidification during ischemia and slower recovery from acidosis after reperfusion.⁶⁹ Although this is strongly suggestive for a role of NHE in pH_i regulation during ischemia per se, other investigators have failed to demonstrate this effect of ethylisobutylamiloride on pH_i despite the ability of this drug to attenuate sodium loading and improve ventricular recovery,⁷⁰ possibly because of other pH-regulatory processes such as Na⁺-HCO₃ symport (see Introduction), to compensate for NHE inhibition.

Cardioprotective Effects of NHE Inhibitors
Very strong support for NHE involvement in cardiac injury has originated from studies that have used drugs that inhibit the antiporter. Indeed, such evidence is very compelling, with protective effects of NHE inhibitors being extensively demonstrated in numerous studies. As summarized in the Table, these effects have been shown with respect to a large number of parameters of cardiac function, including enhanced contractility, reduced contracture, and a decrease in the incidence of arrhythmias, as well as in clinical studies. In addition, improvements in biochemical and ultrastructural indices have been extensively demonstrated with NHE inhibition. The first study demonstrating protection was reported from our laboratory,⁷¹ which showed that amiloride, the prototypical NHE inhibitor, enhanced ventricular recovery, and diminished enzyme efflux from reperfused ischemic isolated rat hearts. We have also shown that the protective effect of amiloride is associated with reduced incidence of arrhythmias and preservation of ultrastructural integrity.⁷² Early studies have shown that this protection is associated with diminished tissue contents of Na⁺ and Ca²⁺, in support of a close association between NHE and Na⁺-Ca²⁺ exchange activity.⁷³ More recent studies have used more specific and potent benzoylguanidine NHE inhibitors, such as the HOE compounds, to demonstrate protection and implicate NHE involvement. For example, the first such agent, HOE 694, has been shown to exert protective effects in terms of virtually all parameters studied both under in vitro conditions and in animals subjected to coronary artery occlusion and reperfusion.^{74 75 76 77 78 79 80} Interestingly, HOE 694 and ethylisobutylamiloride were equally effective as antiarrhythmic agents when administered only at reperfusion.⁷⁹ It has been proposed that buffer composition may explain some of the controversy concerning the locus of action of NHE inhibitors (ie, during ischemia or reperfusion [see below]), because NHE inhibitors exerted protective effects irrespective of time of addition when hearts were perfused with bicarbonate-free medium, whereas addition before ischemia was a prerequisite for protection with bicarbonate-containing medium.⁸⁰

View this table: [in this window] [in a new window]   Table 1. Major Beneficial Effects of NHE Inhibitors in the Ischemic Myocardium in Experimental and Clinical Studies

HOE 642 (cariporide), a potent NHE1-selective inhibitor, exerts marked protective effects in various experimental models and in terms of numerous parameters under both in vitro and in vivo situations.^{53 81 82 83 84 85 86 87 88 89} This may explain the relatively rapid development of this drug for clinical use as a cardioprotective strategy (see below). Likewise, the benzoylguanidine compound EMD 85131 has recently been shown to exert potent infarct-reducing effects in a canine occlusion-reperfusion model, which has also resulted in its entry into the clinical arena.⁹⁰

Locus of Protection
Although it is not completely certain whether prereperfusion treatment with NHE inhibitors is necessary for myocardial protection, most studies suggest that this is indeed a major requirement. We initially reported that amiloride failed to improve recovery of isolated ischemic rat hearts when administered only at reflow.⁷¹ In addition, HOE 694 was ineffective both in blood-perfused isolated ischemic rabbit hearts⁷⁵ and in porcine hearts⁷⁶ when it was administered solely at reperfusion. In other studies, amiloride or amiloride analogues exerted diminished protection but were not completely ineffective in protecting the reperfused heart when added only during reperfusion compared with protection seen with drug pretreatment before ischemia.^{73 91} Others have shown good protective effects of a variety of amiloride analogs in reperfused right ventricular tissue irrespective of drug addition protocols, which are independent of whether the agents were administered before ischemia or on reperfusion,^{92 93} a finding that is in agreement with the theoretical concept that maximum activation of NHE occurs at reperfusion. Indeed, in posthypoxic reoxygenated rat ventricular myocytes, HOE 694 added at reoxygenation attenuated the development of contracture and Ca²⁺ oscillations by prolonging intracellular acidosis during this period.⁶⁴ Although specific NHE1 inhibitors, including cariporide⁸² and EMD 85131,⁹⁰ reduce infarct size when administered in late ischemia, protection is markedly greater when given before coronary occlusion. A recent report, however, showed a lack of protection when cariporide was administered immediately before reperfusion after coronary artery occlusion in the pig.⁸⁵ The superior protection with NHE inhibitors present during ischemia reflects the ability of these agents to inhibit injury in the ischemic nonreperfused myocardium, as discussed above. It can therefore be concluded that NHE inhibitors protect when administered before reperfusion, although for optimal protection, drug administration during both ischemia and reperfusion appears to be a critical prerequisite.

NHE and Apoptosis
Increasing evidence that apoptosis is an important response of the myocardium to ischemia, which is rapid, precedes cell necrosis, and appears to contribute the overall sequela of cardiac injury [reviewed in Reference ⁹⁴ ]. NHE inhibitors can attenuate apoptosis in a variety of models, including myocytes subjected to metabolic inhibition,⁹⁵ ischemic and reperfused isolated hearts,⁹⁶ and in vivo coronary artery occlusion⁵³ ; however, the precise mechanism for this effect remains to be determined.

NHE and Ischemic Preconditioning
One of the characteristics of ischemic preconditioning is diminished acidosis during ischemia,⁹⁷ which is associated with reduced [Na⁺]_i and [Ca²⁺]_i content.⁹⁸ It has been proposed that reduced acidosis reflects stimulated NHE,⁹⁹ and in a calcium-induced preconditioning model dimethylamiloride blocks the cardioprotective effects.¹⁰⁰ However, these findings represent a paradoxical argument against the numerous studies showing benefits of NHE inhibitors. Moreover, inhibition of NHE in the preconditioned myocardium does not abolish the reduced acidosis, which suggests that the latter is NHE independent.¹⁰¹ Furthermore, NHE inhibition fails to alter the cardioprotective effects of ischemic preconditioning and offers additive protective effects,^{84 102} and the protection by NHE inhibition occurs via a mechanism different from preconditioning.⁸³

Further evidence that the protective effect of NHE inhibitors differs from that produced by ischemic preconditioning reflects the apparent superior ability produced by the former approach. For example, a recent study demonstrated that the salutary effects of preconditioning in terms of infarct size reduction are overcome with prolonged (90 minutes) coronary artery occlusion of the canine myocardium, whereas protection with NHE inhibition is still maintained.¹⁰³

Role of NHE in Cardiac Injury Produced by Ischemic Metabolites
In addition to NHE activation due to acidosis, further antiport activation could occur because of direct stimulation by metabolites produced by the ischemic myocardium. For example, endothelin-1 (ET-1) levels are elevated in myocardial ischemia, which can produce deleterious effects on the reperfused myocardium in terms of inducing both diastolic and systolic abnormalities.¹⁰⁴ ET-1 is a potent NHE activator, a property that may account for the positive inotropic effects of the peptide. Indeed, the toxicity produced by ET-1 can be attenuated by NHE inhibition, suggesting an important role of the antiporter in mediating the detrimental effect of the peptide on the ischemic and reperfused myocardium.¹⁹ NHE activation may also represent an important mechanism for development of arrhythmogenesis in the reperfused myocardium, particularly under conditions of elevated catecholamine levels. For example, ₁-adrenergic agonists enhance ventricular arrhythmias in the reperfused ischemic myocardium, which can be markedly decreased by NHE inhibition.¹⁰⁵

In addition to a direct protective effect of NHE inhibitors on the ischemic and reperfused heart, we have also demonstrated that the NHE may also explain the initial observation by Neely and Grotyohann¹⁰⁶ that inhibition of glycolytic flux by glycogen depletion results in improved postischemic ventricular recovery, presumably as a result of reduction in the lactate burden at the end of ischemia, given that exogenous lactate reversed the protection. Whether the role of lactate is proton dependent remains uncertain, particularly as the contribution of lactate to intracellular acidosis in the ischemic myocardium is controversial.¹⁰⁷ However, it is interesting that inhibition of lactate accumulation in the ischemic myocardium mimics the effects of amiloride in terms of postischemic contractile recovery as well as Na⁺ and Ca²⁺ accumulation after reperfusion.⁷³ Moreover, lactate-induced reduction in contractile recovery after reperfusion is reversed by NHE inhibitors.¹⁰⁸ Whereas these observations are suggestive of NHE involvement in the lactate-induced depression in postischemic recovery, it should be noted that pH_i was not measured in these studies to confirm enhanced ischemia-induced acidosis by lactate.^{73 106 108} Therefore, the relationship among lactate-induced attenuation of postischemic recovery, pH_i, and NHE activity remains to be determined.

We recently reported that lysophosphatidylcholine is a potent NHE activator in the cardiac cell and that the cardiotoxic effects, at least at low concentrations of this amphiphile, can be markedly attenuated by NHE inhibitors.³² Moreover, we have demonstrated that direct toxicity produced by hydrogen peroxide¹⁰⁹ or the ability of low concentrations of hydrogen peroxide to depress postischemic recovery¹¹⁰ can be attenuated by NHE inhibition.

Clinical Development and Evaluation of NHE Inhibitors in the Treatment of Coronary Heart Disease
The preliminary results of the first clinical evaluation of NHE inhibition were recently presented at the 48th Annual Scientific Session of the American College of Cardiology. The GUARDIAN (Guard During Ischemia Against Necrosis) study, a Phase II/Phase III double-blind, randomized placebo-controlled study of >11 500 patients, assessed different doses of cariporide in individuals with acute coronary syndromes. The study failed to demonstrate an overall significant attenuation (10%) of the 2 primary events, mortality and incidence of myocardial infarction; however, favorable effects among the 3 major subgroups were observed in those patients receiving the highest dose (120 mg every 8 hours) of the drug, including a significant event rate reduction in high-risk patients undergoing coronary artery bypass surgery. These results are therefore encouraging, especially given that the study also represented a dose-finding component, and overall supports the concept that NHE inhibition represents a safe, therapeutic approach for cardioprotection that undoubtedly deserves future attention. Indeed, the NHE1-selective inhibitor eniporide (EMD 96785) developed by Merck KGaA has been shown to be well tolerated in Phase I trials and is currently being investigated in a Phase II 800 to 1200 patient placebo-controlled trial, the ESCAMI (Evaluation of the Safety and the Cardioprotective Effects of Eniporide in Acute Myocardial Infarction) study in which the drug is administered before angioplasty or thrombolysis. An interim analysis based on >400 patients was performed in late May 1999, at which time it was concluded that the study will continue. Additionally, results with cariporide in a relatively small clinical trial with 100 patients indicate that the drug has the ability to improve left ventricular function when administered before balloon angioplasty in patients with acute myocardial infarction.¹¹¹ Taken together, there has been a rather rapid evolution of progress in the development of novel therapeutic strategies for treating coronary heart disease, although further clinical assessment is still required.

	NHE and Other Cardiac Disease States

Top Abstract Introduction NHE1 Structure and Cellular... Regulation of NHE1 Activity Transcriptional Regulation of... NHE1 in the Ischemic... NHE and Other Cardiac... Conclusions References

 
Diabetic Myocardium
Myocardial NHE1 activity in diabetes appears to be depressed, possibly because of reduced calcium/calmodulin II–dependent phosphorylation of the antiporter,¹¹² and recovery from ischemia-induced acidosis in the diabetic heart is less dependent on NHE and more on bicarbonate-dependent processes.¹¹³ Depressed NHE activity may explain increased resistance of diabetic hearts to ischemia and reperfusion.^{114 115}

Cardiac Hypertrophy and Heart Failure
The ability of pH_i to affect protein synthesis renders NHE a potentially important target for the regulation of cell proliferation and hypertrophy through pharmacological approaches. Indeed, there is now compelling evidence from studies using a variety of tissues that cell growth and proliferation may be regulated by NHE and that NHE inhibitors can block such responses. Of particular interest are reports that neointimal thickening and smooth muscle cell proliferation after carotid artery balloon injury are mitigated by NHE inhibitors.^{116 117} Moreover, angiotensin II–induced vascular smooth muscle cell hypertrophy appears to be mediated by NHE.¹¹⁸ Thus, NHE inhibitors could be potentially useful for the attenuation of atherosclerotic lesion development and restenosis.

As shown in Figure 2, NHE represents a key downstream factor activated by a variety of hypertrophic stimuli. Indeed, in cardiac cells, NHE inhibitors block hypertrophic responses to various stimuli. Stretch-induced stimulation in protein synthesis in neonatal cardiac myocytes as well as stretch-induced alkalinization in feline papillary muscles can be blocked by NHE inhibitors,^{119 120} as can norepinephrine-induced protein synthesis in cultured rat cardiomyocytes.¹²¹ Orally administered amiloride, a nonspecific NHE inhibitor, reduces fiber diameter in rat coronary ligation¹²² and murine dilated cardiomyopathy models.¹²³ We have recently found that dietary administration of cariporide completely abrogates the increased length of surviving myocytes after 1 week after coronary artery occlusion and ameliorates contractile dysfunction in the absence of afterload or infarct size reduction.¹²⁴ Thus, it appears that numerous endogenous factors that have been implicated in the ventricular remodeling/heart failure process also activate NHE. It is unlikely that the antiport is the only intracellular messenger mediating such responses, although it has been suggested that NHE may therefore serve as an important downstream regulator contributing to remodeling in response to various hypertrophic factors.¹²⁵ Interestingly, however, it has recently been shown that the ability of both endothelin-1 and angiotensin II to activate NHE is impaired in rat cardiac myocytes from hypertrophied hearts caused by aortic banding, a finding attributed to defective coupling between PKC and NHE activation.²¹ A similar observation, at least with respect to angiotensin II, has been demonstrated in surviving ventricular myocytes from chronically infarcted rabbit myocardium, suggesting that this defective coupling may not be dependent on species or hypertrophic model.¹²⁶ The relevance of these findings remains to be determined, although it is attractive to suggest that they may reflect potential protective compensatory responses aimed at attenuating the potential deleterious effect of stimulated NHE activation.

	Conclusions

Top Abstract Introduction NHE1 Structure and Cellular... Regulation of NHE1 Activity Transcriptional Regulation of... NHE1 in the Ischemic... NHE and Other Cardiac... Conclusions References

 
The past 11 years have seen impressive progress in the understanding of the regulation of NHE in terms of activity and transcriptional regulation. In the domain of cardiac research, there has emerged virtually undisputable evidence that NHE activation in the ischemic and reperfused heart plays a major role in restoring pH_i, which at the same contributes to tissue damage. Accordingly, NHE inhibition has been demonstrated in numerous experimental studies to protect the myocardium, which has translated into initial clinical evaluation. In addition to its role in acute ischemia and reperfusion, the antiporter is likely of importance in other cardiac disease states, the most compelling of which appear to be postinfarction myocardial remodeling, hypertrophy, and evolution to heart failure. Much work needs to be done in this regard, particularly in terms of understanding of the regulation of NHE in chronic responses and how the system can be ideally modulated for therapeutic strategies, either alone or as adjunctive therapy with other treatment modalities.

	Acknowledgments

 
Studies cited from the authors' laboratory are supported by the Medical Research Council of Canada. Dr Karmazyn is a recipient of a Heart and Stroke Foundation of Ontario Career Investigator Award.

Received April 30, 1999; accepted August 19, 1999.

	References

Top Abstract Introduction NHE1 Structure and Cellular... Regulation of NHE1 Activity Transcriptional Regulation of... NHE1 in the Ischemic... NHE and Other Cardiac... Conclusions References

 
1. Leem CH, Lagadic-Gossmann D, Vaughan-Jones RD. Characterization of intracellular pH in the guinea-pig ventricular myocyte. J Physiol. 1999;517:159–180.[Abstract/Free Full Text]

2. Wakabayashi S, Shigekawa M, Pouysségur J. Molecular physiology of vertebrate Na⁺/H⁺ exchangers. Physiol Rev. 1997;77:51–74.[Abstract/Free Full Text]

3. Fliegel L, Fröhlich O. The Na⁺/H⁺ exchanger: an update on structure, regulation and cardiac physiology. Biochem J. 1993;296:273–285.

4. Orlowski J, Grinstein S. Na⁺/H⁺ exchangers of mammalian cells. J Biol Chem. 1997;272:22373–22376.[Free Full Text]

5. Numuta M, Petrecca K, Lake N, Orlowski J. Identification of a mitochondrial Na⁺/H⁺ exchanger. J Biol Chem. 1998;273:6951–6959.[Abstract/Free Full Text]

6. Nass R, Rao R. Novel localization of a Na⁺/H⁺ exchanger in a late endosomal compartment of yeast: implications for vacuole biogenesis. J Biol Chem. 1998;273:21054–21060.[Abstract/Free Full Text]

7. Orlowski J, Kandasamy RA, Shull GE. Molecular cloning of putative members of the Na/H exchanger gene family. J Biol Chem. 1992;267:9331–9339.[Abstract/Free Full Text]

8. Aronson PS. Kinetic properties of the plasma membrane Na⁺-H⁺ exchanger. Annu Rev Physiol. 1985;47:545–560.[Medline] [Order article via Infotrieve]

9. Counillon L, Pouysségur J. Structure-function studies and molecular regulation of the growth factor activatable sodium-hydrogen exchanger (NHE-1). Cardiovasc Res. 1995;29:147–154.[Medline] [Order article via Infotrieve]

10. Kandasamy RA, Yu FH, Harris R, Boucher A, Hanrahan JW, Orlowski J. Plasma membrane Na⁺/H⁺ exchanger isoforms (NHE-1, -2, and -3) are differentially responsive to second messenger agonists of the protein kinase A and C pathways. J Biol Chem. 1995;270:29209–29216.[Abstract/Free Full Text]

11. Nath SK, Hang CY, Levine SA, Yun CH, Montrose MH, Donowitz M, Tse CM. Hyperosmolarity inhibits the Na⁺/H⁺ exchanger isoforms NHE2 and NHE3: an effect opposite to that on NHE1. Am J Physiol. 1996;270:G431–G441.[Abstract/Free Full Text]

12. Petrecca K, Atanasiu R, Grinstein S, Orlowski J, Shrier A. Subcellular localization of the Na⁺/H⁺ exchanger NHE1 in rat myocardium. Am J Physiol. 1999;276:H709–H717.[Abstract/Free Full Text]

13. Wu ML, Vaughan-Jones RD. Interaction between Na⁺ and H⁺ ions on Na-H exchange in sheep cardiac Purkinje fibers. J Mol Cell Cardiol. 1997;29:1131–1140.[Medline] [Order article via Infotrieve]

14. Lagadic-Gossman D, Buckler KJ, Vaughan-Jones RD. Role of bicarbonate in pH recovery from intracellular acidosis in the guinea-pig ventricle myocyte. J Physiol. 1992;458:361–384.[Abstract/Free Full Text]

15. Fliegel L, ed. The Na⁺/H⁺ Exchanger. Austin, Tex: RG Landes Company; 1996.

16. Bianchini L, Pouysségur J. Regulation of the Na⁺/H⁺ exchanger isoform NHE1: role of phosphorylation. Kidney Int. 1996;49:1038–1041.[Medline] [Order article via Infotrieve]

17. Kinsella JL, Heller P, Fröhlich JP. Na⁺/H⁺ exchanger: proton modifier site regulation of activity. Biochem Cell Biol. 1998;76:743–749.[Medline] [Order article via Infotrieve]

18. Bianchini L, L'Allemain G, Pouysségur J. The p42/p44 mitogen-activated protein kinase cascade is determinant in mediating activation of the Na⁺/H⁺ exchanger (NHE1 isoform) in response to growth factors. J Biol Chem. 1997;272:271–279.[Abstract/Free Full Text]

19. Khandoudi N, Ho J, Karmazyn M. Role of sodium/hydrogen exchange in mediating the effects of endothelin-1 on the normal and ischemic and reperfused heart. Circ Res. 1994;75:369–378.[Abstract/Free Full Text]

20. Wu ML, Tseng YZ. The modulatory effects of endothelin-1, carbachol and isoprenaline upon Na⁺-H⁺ exchange in dog cardiac Purkinje fibers. J Physiol. 1993;471:583–597.[Abstract/Free Full Text]

21. Ito N, Kagaya Y, Weinberg EO, Barry WH, Lorell BH. Endothelin and angiotensin II stimulation of Na⁺-H⁺ exchange is impaired in cardiac hypertrophy. J Clin Invest. 1997;99:125–135.[Medline] [Order article via Infotrieve]

22. Woo SH, Lee CO. Effects of endothelin-1 on Ca²⁺ signaling in guinea pig ventricular myocytes: role of protein kinase C. J Mol Cell Cardiol. 1999;31:631–643.[Medline] [Order article via Infotrieve]

23. Matsui H, Barry WH, Livsey C, Spitzer KW. Angiotensin II stimulates sodium-hydrogen exchange in adult rabbit ventricular myocytes. Cardiovasc Res. 1995;29:215–221.[Medline] [Order article via Infotrieve]

24. Boston DR, Koyama T, Rodriguez-Larrain J, Zou A, Su Z, Barry WH. Effects of angiotensin II on intracellular calcium and contracture in metabolically inhibited cardiomyocytes. J Pharmacol Exp Ther. 1998;285:716–723.[Abstract/Free Full Text]

25. Mattiazi A, Perez NG, Vila-Petrof MG, Alvarez B, Camillon De Hurtado MC, Cingolani HE. Dissociation between positive inotropic and alkalinizing effects of angiotensin II in feline myocardium. Am J Physiol. 1997;272:H1131–H1136.[Abstract/Free Full Text]

26. Wallert MA, Fröhlich O. ₁-Adrenergic stimulation of the Na-H exchange in cardiac myocytes. Am J Physiol. 1992;263:C1096–C1102.[Abstract/Free Full Text]

27. Puçéat M, Vassort G. Neurohumoral modulation of intracellular pH in the heart. Cardiovasc Res. 1995;29:178–183.[Medline] [Order article via Infotrieve]

28. Yokoyama H, Yasutake M, Avkiran M. ₁-Adrenergic stimulation of sarcolemmal Na⁺-H⁺ exchanger activity in rat ventricular myocytes: evidence for selective mediation by the _1A-adrenoceptor subtype. Circ Res. 1998;82:1078–1085.[Abstract/Free Full Text]

29. Yasutake M, Haworth RS, King A, Avkiran M. Thrombin activates the sarcolemmal Na⁺-H⁺ exchanger: evidence for a receptor-mediated mechanism involving protein kinase C. Circ Res. 1996;79:705–715.[Abstract/Free Full Text]

30. Wakabayashi S, Fafournoux P, Sardet C, Pouysségur J. The Na⁺/H⁺ antiporter cytoplasmic domain mediates growth factor signals and controls "H" sensing. Proc Natl Acad Sci U S A. 1992;89:2424–2428.[Abstract/Free Full Text]

31. Sabri A, Byron KL, Samarel AM, Bell Lucchesi PA. Hydrogen peroxide activates mitogen-activated protein kinases and Na⁺-H⁺ exchange in neonatal rat cardiac myocytes. Circ Res. 1998;82:1053–1062.[Abstract/Free Full Text]

32. Hoque ANE, Haist JV, Karmazyn M. Na⁺-H⁺ exchange inhibition protects against mechanical, ultrastructural, and biochemical impairment induced by low concentrations of lysophosphatidylcholine in isolated rat hearts. Circ Res. 1997;80:95–102.[Abstract/Free Full Text]

33. Siczkowski M, Ng LL. Phorbol ester activation of the rat vascular myocyte Na⁺/H⁺ exchanger isoform I. Hypertension. 1996;27:859–866.[Abstract/Free Full Text]

34. Wang H, Silva NL, Lucchesi PA, Haworth R, Wang K, Michalak M, Pelech S, Fliegel L. Phosphorylation and regulation of the Na⁺/H⁺ exchanger through mitogen-activated protein kinase. Biochemistry. 1997;29:9151–9158.

35. Moor AN, Fliegel L. Protein kinase mediated regulation of the Na⁺/H⁺ exchanger in the rat myocardium by mitogen-activated protein kinase-dependent pathways. J Biol Chem. 1999;274:22985–22992.[Abstract/Free Full Text]

36. Seko Y, Tobe K, Ueki K, Kadowaki T, Yazaki Y. Hypoxia and hypoxia/reoxygenation activate Raf-1, mitogen-activated protein kinase kinase, mitogen-activated protein kinases, and S6 kinase in cultured rat cardiac myocytes. Circ Res. 1996;78:82–90.[Abstract/Free Full Text]

37. Wakabayashi S, Bertrand B, Ikeda T, Pouysségur J, Shigekawa M. Mutation of calmodulin-binding site renders the Na⁺/H⁺ exchanger (NHE1) highly H(⁺)-sensitive and Ca²⁺ regulation-defective. J Biol Chem. 1994;269:13710–13715.[Abstract/Free Full Text]

38. Bertrand B, Wakabayashi S, Ikeda T, Pouysségur J, Shigekawa M. The Na⁺/H⁺ exchanger isoform 1 (NHE1) is a novel member of the calmodulin-binding proteins: identification and characterization of calmodulin-binding sites. J Biol Chem. 1994;269:13703–13709.[Abstract/Free Full Text]

39. Weissberg PL, Little PJ, Cragoe EJ, Bobik A. The pH of spontaneously beating cultured rat heart cells is regulated by an ATP-calmodulin-dependent Na⁺/H⁺ antiport. Circ Res. 1988;64:676–685.[Abstract/Free Full Text]

40. Wu M, Vaughan-Jones RD. Effect of metabolic inhibitors and second messengers upon Na^+-H⁺ exchange in the sheep cardiac Purkinje fibre. J Physiol. 1994;471:583–597.

41. Goss G, Woodside M, Wakabayashi S, Pouysségur J, Waddell T, Downey GP, Grinstein S. ATP dependence of NHE-1, the ubiquitous isoform of the Na⁺/H⁺ antiporter: analysis of phosphorylation and subcellular localization. J Biol Chem. 1994;269:8741–8748.[Abstract/Free Full Text]

42. Aharonovitz O, Demaurex N, Woodside M, Grinstein S. ATP dependence is not an intrinsic property of Na⁺/H⁺ exchanger NHE1: requirement for an ancillary factor. Am J Physiol. 1999;276:C1303–C1311.[Abstract/Free Full Text]

43. Dhanasekaran N, Prasad MV, Wadsworth SJ, Dermott JM, van Rossum G. Protein kinase C-dependent and -independent activation of Na⁺/H⁺ exchanger by G₁₂ class of G proteins. J Biol Chem. 1994;269:11802–11806.[Abstract/Free Full Text]

44. Kitamura K, Singer WD, Cano A, Miller RT. G_q and G₁₃ regulate NHE-1 and intracellular calcium in epithelial cells. Am J Physiol. 1995;268:C101–C110.[Abstract/Free Full Text]

45. Voyno-Yasenetskaya T, Conklin BR, Gilbert RL, Hooley R, Bourne HR, Barber DL. G₁₃ stimulates Na-H exchange. J Biol Chem. 1994;269:4721–4724.[Abstract/Free Full Text]

46. Hooley R, Yu C, Symons M, Barber DL. G₁₃ stimulates Na⁺-H⁺ exchange through distinct cdc41-dependent and RhoA-dependent pathways. J Biol Chem. 1996;271:6152–6158.[Abstract/Free Full Text]

47. Kolyada AY, Lebedeva TV, Johns CA, Madias NE. Proximal regulatory elements and nuclear activities required for transcription of the human Na⁺/H⁺ exchanger (NHE-1) gene. Biochim Biophys Acta. 1994;1217:54–64.[Medline] [Order article via Infotrieve]

48. Dyck JRB, Silva NLCL, Fliegel L. Activation of the Na⁺/H⁺ exchanger gene by the transcription factor AP-2. J Biol Chem. 1995;270:1375–1381.[Abstract/Free Full Text]

49. Yang W, Dyck JRB, Wang H, Fliegel L. Regulation of the NHE-1 promoter in mammalian myocardium. Am J Physiol. 1996;270:H259–H266.[Abstract/Free Full Text]

50. Yang W, Wang H, Fliegel L. Regulation of Na⁺/H⁺ exchanger gene expression: Role of a novel poly(dA · dT) element in regulation of the NHE1 promoter. J Biol Chem. 1996;271:20444–20449.[Abstract/Free Full Text]

51. Dyck JR, Maddaford TG, Pierce GN, Fliegel L. Induction of expression of the sodium-hydrogen exchanger in rat myocardium. Cardiovasc Res. 1995;29:203–208.[Medline] [Order article via Infotrieve]

52. Gan XT, Chakrabarti S, Karmazyn M. Modulation of Na⁺-H⁺ exchange isoform 1 mRNA expression in isolated rat hearts. Am J Physiol. 1999;277:H993–H998.[Abstract/Free Full Text]

53. Humphreys, RA, Haist JV, Chakrabarti S, Feng QP, Arnold JMO, Karmazyn, M. Orally administered NHE1 inhibitor cariporide reduces acute responses to coronary occlusion and reperfusion. Am J Physiol. 1999;276:H749–H757.[Abstract/Free Full Text]

54. Frelin C, Vigne P, Lazdunski M. The role of the Na⁺/H⁺ exchange system in cardiac cells in relation to the control of the internal Na⁺ concentration: a molecular basis for the antagonistic effect of ouabain and amiloride on the heart. J Biol Chem. 1984;259:8880–8885.[Abstract/Free Full Text]

55. Kim D, Smith TW. Effects of amiloride and ouabain on contractile state, Ca and Na fluxes, and Na content in cultured chick heart cells. Mol Pharmacol. 1986;29:363–371.[Abstract]

56. Finet M, Godfraind T. Selective inhibition by ethylisopropylamiloride of the positive inotropic effect evoked by low concentrations of ouabain in rat isolated ventricles. Br J Pharmacol. 1986;89:533–538.[Medline] [Order article via Infotrieve]

57. 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.[Medline] [Order article via Infotrieve]

58. Frelin C, Vigne P, Ladoux A, Lazdunski M. The regulation of the intracellular pH in cells from vertebrates. Eur J Biochem. 1988;174:3–14.[Medline] [Order article via Infotrieve]

59. Piwnica-Worms D, Jacob R, Shigeto N, Horres, Lieberman M. Na/H exchange in cultured heart cells: secondary stimulation of electrogenic transport during recovery from intracellular acidosis. J Mol Cell Cardiol. 1986;18:1109–1116.[Medline] [Order article via Infotrieve]

60. Kim D, Cragoe EJ, Smith TW. Relations among sodium pump inhibition, Na-Ca and Na-H exchange activities and Ca-H interactions in cultured chick heart cells. Circ Res. 1987;60:185–193.[Abstract/Free Full Text]

61. Siffert W, Akkerman JWN. Na⁺/H⁺ exchange and Ca²⁺ influx. FEBS Lett. 1989;259:1–4.[Medline] [Order article via Infotrieve]

62. Piwnica-Worms D, Jacob R, Horres CR, Lieberman M. Na/H exchange in cultured chick heart cells. J Gen Physiol. 1985;85:43–64.[Abstract/Free Full Text]

63. Duan J, Moffat MP. Contractile and electrophysiological effects of realkalization in cardiac tissue: role of Na/H exchange and increased [Ca]_i. Adv Exp Med Biol. 1992;311:435–436.[Medline] [Order article via Infotrieve]

64. Ladilov YV, Siegmund B, Piper HM. Protection of reoxygenated cardiomyocytes against hypercontracture by inhibition of Na⁺/H⁺ exchange. Am J Physiol. 1995;268:H1531–H1539.[Abstract/Free Full Text]

65. 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.[Abstract/Free Full Text]

66. Lemasters JJ, Bond JM, Chacon E, Harper IS, Kaplan SH, Ohata H, Trollinger DR, Herman B, Cascio WE. The pH paradox in ischemia-reperfusion injury to cardiac myocytes. In: Karmazyn M, ed. Myocardial Ischemia: Mechanisms, Reperfusion, Protection. Basel, Switzerland: Birkhäuser; 1996:99–114.

67. Harper IS, Bond JM, Chacon E, Reece JM, Herman B, Lemasters JJ. Inhibition of Na⁺/H⁺ exchange preserves viability, restores mechanical function, and prevents the pH paradox in reperfusion injury to rat neonatal myocytes. Basic Res Cardiol. 1993;88:430–442.[Medline] [Order article via Infotrieve]

68. Murphy E, Perlman M, London RE, Steenbergen C. Amiloride delays the ischemia-induced rise in cytosolic calcium. Circ Res. 1991;68:1250–1258.[Abstract/Free Full Text]

69. Koike A, Akita T, Hotta Y, Takeyka K, Kodama I, Murase M, Abe T, Toyama J. Protective effects of dimethyl amiloride against postischemic myocardial dysfunction in rabbit hearts: phosphorus 31-nuclear magnetic resonance measurements of intracellular pH and cellular energy. J Thorac Cardiovasc Surg. 1996;112:765–775.[Abstract/Free Full Text]

70. Navon G, Werrmann JG, Maron R, Cohen SM. ³¹P NMR and triple quantum filtered ²³Na NMR studies of the effects of inhibition of Na⁺/H⁺ exchange on intracellular sodium and pH in working and ischemic hearts. Magn Reson Med. 1994;32:556–564.[Medline] [Order article via Infotrieve]

71. Karmazyn M. Amiloride enhances postischemic ventricular recovery: possible role of Na⁺/H⁺ exchange. Am J Physiol. 1988;255:H608–H615.[Abstract/Free Full Text]

72. Duan J, Karmazyn M. Protective effects of amiloride on the ischemic reperfused rat heart: relation to mitochondrial function. Eur J Pharmacol. 1992;210:149–157.[Medline] [Order article via Infotrieve]

73. Tani M, Neely JR. Role of intracellular Na⁺ in 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.[Abstract/Free Full Text]

74. Scholz W, Albus U, Lang HJ, Linz W, Martorana P, Englert HC, Schölkens BA. Hoe 694, a new Na⁺/H⁺ exchange inhibitor in cardiac ischaemia. Br J Pharmacol. 1993;109:562–568.[Medline] [Order article via Infotrieve]

75. Hendrikx M, Mubagwa K, Verdonck F, Overloop K, Van Hecke P, Vanstapel F, Van Lommel A, Verbeken E, Lauweryns J, Flameng W. New Na⁺-H⁺ exchange inhibitor HOE 694 improves postischemic function and high-energy phosphate resynthesis and reduces Ca²⁺ overload in isolated perfused rabbit heart. Circulation. 1994;89:2787–2798.[Abstract/Free Full Text]

76. Klein HH, Pich S, Bohle RM, Wollenweber J, Nebendahl K. Myocardial protection by Na⁺-H⁺ exchange inhibition in ischemic, reperfused porcine hearts. Circulation. 1995;92:912–917.[Abstract/Free Full Text]

77. Xue YX, Aye NN, Hashimoto K. Antiarrhythmic effects of HOE642, a novel Na⁺-H⁺ exchange inhibitor, on ventricular arrhythmias in animal hearts. Eur J Pharmacol. 1996;317:309–316.[Medline] [Order article via Infotrieve]

78. Sack S, Mohri M, Schwarz ER, Arras M, Schaper J, Ballagi-Pordány G, Scholz W, Lang HJ, Schölkens BA, Schaper W. Effects of a new Na⁺/H⁺ antiporter inhibitor on postischemic reperfusion in pig heart. J Cardiovasc Pharmacol. 1994;23:72–78.[Medline] [Order article via Infotrieve]

79. Yasutake M, Ibuki C, Hearse DJ, Avkiran M. Na⁺/H⁺ exchange and reperfusion arrhythmias: protection by intracoronary infusion of a novel inhibitor. Am J Physiol. 1994;267:H2430–H2440.[Abstract/Free Full Text]

80. Shimada Y, Hearse DJ, Avkiran M. Impact of extracellular buffer composition on cardioprotective efficacy of Na⁺/H⁺ exchange inhibitors. Am J Physiol. 1996;270:H692–H700.[Abstract/Free Full Text]

81. Scholz W, Albus U, Counillon L, Gögelein H, Lang H-J, Linz W, Weichert A, Schölkens BA. Protective effect of HOE 642, a selective sodium-hydrogen exchange subtype 1 inhibitor, on cardiac ischaemia and reperfusion. Cardiovasc Res. 1995;29:260–268.[Medline] [Order article via Infotrieve]

82. Linz W, Albus U, Crause P, Jung W, Weichert A, Schölkens BA, Scholz W. Dose-dependent reduction of myocardial infarct mass in rabbits by the NHE-1 inhibitor cariporide (HOE 642). Clin Exp Hypertens. 1998;20:733–749.

83. Miura T, Ogawa T, Suzuki K, Goto M, Shimamoto K. 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 Cardiol. 1997;29:693–701.[Abstract]

84. Shipolini AR, Yokoyama H, Galianes M, Edmondson SJ, Hearse DJ, Avkiran M. Na⁺/H⁺ exchanger activity does not contribute to protection by ischemic preconditioning in the isolated rat heart. Circulation. 1997;96:3617–3625.[Abstract/Free Full Text]

85. Garcia-Dorado D, Gonzales MA, Barrabes JA, Ruiz-Meana M, Solares J, Lidon RM, Blanco J, Puigfel Y, Piper HM, Soler-Soler J. Prevention of ischemic rigor contracture during coronary occlusion by inhibiting of Na⁺-H⁺ exchange. Cardiovasc Res. 1997;35:80–89.[Abstract/Free Full Text]

86. Mathur S, Karmazyn M. Interaction between anesthetics and the sodium-hydrogen exchange inhibitor 642 (cariporide) in ischemic and reperfused rat hearts. Anesthesiology. 1997;87:1460–1469.[Medline] [Order article via Infotrieve]

87. Eng S, Maddaford TG, Kardami E, Pierce GN. Protection against myocardial ischemic/reperfusion injury by inhibitors of two separate pathways of Na⁺ entry. J Mol Cell Cardiol. 1998;30:829–835.[Medline] [Order article via Infotrieve]

88. Klein H, Bohle RM, Pich S, Lindert-Heimberg S, Wollenweber J, Schade-Brittinger C, Nebendahl K. Time-dependent protection by Na⁺/H⁺ exchange inhibition in a regionally ischemic, reperfused porcine heart preparation with low residual flow. J Mol Cell Cardiol. 1998;30:795–801.[Medline] [Order article via Infotrieve]

89. Dhein S, Krusemann K, Engelmann F, Gottwald M. Effects of the type-1 Na⁺/H⁺ exchange inhibitor cariporide (Hoe 642) on cardiac tissue. Naunyn Schmiedebergs Arch Pharmacol. 1998;357:662–670.[Medline] [Order article via Infotrieve]

90. Gumina RJ, Mizumura T, Beier N, Schelling P, Schultz JJ, Gross GJ. A new sodium/hydrogen exchange inhibitor, EMD 85131, limits infarct size in dogs when administered before or after coronary artery occlusion. J Pharmacol Exp Ther. 1998;286:175–183.[Abstract/Free Full Text]

91. Moffat MP, Karmazyn M. Protective effects of the potent Na/H exchange inhibitor methylisobutyl amiloride against post-ischemic contractile dysfunction in rat and guinea-pig hearts. J Mol Cell Cardiol. 1993;25:959–971.[Medline] [Order article via Infotrieve]

92. Meng H-P, Maddaford TG, Pierce GN. Effect of amiloride and selected analogues on postischemic recovery of cardiac contractile function. Am J Physiol. 1993;264:H1831–H1835.[Abstract/Free Full Text]

93. Maddaford TG, Pierce GN. Myocardial dysfunction is associated with activation of Na⁺/H⁺ exchange immediately during reperfusion. Am J Physiol. 1997;273:H2232–H2239.[Abstract/Free Full Text]

94. MacLellan WR, Schneider MD. Death by design: programmed cell death in cardiovascular biology and disease. Circ Res. 1997;81:137–144.[Abstract/Free Full Text]

95. Gottlieb RA, Gruol DL, Zhu JY, Engler RL. Preconditioning in rabbit cardiomyocytes: role of pH, vacuolar proton ATPase, and apoptosis. J Clin Invest. 1996;97:2391–2398.[Medline] [Order article via Infotrieve]

96. Chakrabarti S, Hoque ANE, Karmazyn M. A rapid ischemia-induced apoptosis in isolated rat hearts and its attenuation by the sodium-hydrogen exchange inhibitor HOE 642 (Cariporide). J Mol Cell Cardiol. 1997;29:3169–3174.[Medline] [Order article via Infotrieve]

97. Asimakis GK, Inners-McBride K, Medellin G, Conti VR. Ischemic preconditioning attenuates acidosis and postischemic dysfunction in isolated rat heart. Am J Physiol. 1992;263:H887–H894.[Abstract/Free Full Text]

98. Steenbergen C, Perlman ME, London RE, Murphy E. Mechanisms of preconditioning: ionic alterations. Circ Res. 1993;72:112–135.[Abstract/Free Full Text]

99. Ramasamy R, Liu H, Anderson S, Lundmark K, Schaefer S. Ischemic preconditioning stimulates sodium and proton transport in isolated rat hearts. J Clin Invest. 1998;96:1464–1472.

100. Przyklenk K, Hata K, Kloner RA. Is calcium a mediator of infarct size reduction with preconditioning in canine myocardium? Circulation. 1997;96:1305–1312.[Abstract/Free Full Text]

101. Gabel SA, Cross HR, London RE, Steenbergen C, Murphy E. Decreased intracellular pH is not due to increased H⁺ extrusion in preconditioned rat hearts. Am J Physiol. 1997;273:H2257–H2262.[Abstract/Free Full Text]

102. Bugge E, Ytrehus K. Inhibition of sodium-hydrogen exchange reduces infarct size in the isolated rat heart: a protective additive to ischaemic preconditioning. Cardiovasc Res. 1995;29:269–274.[Medline] [Order article via Infotrieve]

103. Gumina RJ, Buerger E, Daemmgen J, Gross GJ. Direct comparison of the cardioprotective efficacy of ischemic preconditioning and Na⁺/H⁺ exchange inhibition. Circulation. 1998;98(suppl I):I-344. Abstract.

104. Karmazyn, M. The role of endothelins in cardiac function in health and disease. In: Karmazyn M, ed. Myocardial Ischemia: Mechanisms, Reperfusion, Protection. Basel, Switzerland: Birkhäuser; 1996:209–230.

105. Yasutake M, Avkiran M. Exacerbation of reperfusion arrhythmias by ₁ adrenergic stimulation: a potential role for receptor mediated activation of sarcolemmal sodium-hydrogen exchange. Cardiovasc Res. 1995;29:222–230.[Medline] [Order article via Infotrieve]

106. Neely JR, Grotyohann LW. Role of glycolytic products in damage to ischemic myocardium: dissociation of adenosine triphosphate levels and recovery of function of reperfused ischemic hearts. Circ Res. 1984;55:816–824.[Abstract/Free Full Text]

107. Cross HR, Clarke K, Opie LH, Radda GK. Is lactate-induced myocardial ischaemic injury mediated by decreased pH or increased intracellular lactate? J Mol Cell Cardiol. 1995;27:1369–1381.[Medline] [Order article via Infotrieve]

108. Karmazyn M. Na⁺/H⁺ exchange inhibitors reverse lactate-induced depression in postischaemic ventricular recovery. Br J Pharmacol. 1993;108:50–56.[Medline] [Order article via Infotrieve]

109. Hoque ANE, Karmazyn M. Effect of sodium-hydrogen exchange inhibition on functional and metabolic impairment produced by oxidative stress in the isolated rat heart. Can J Physiol Pharmacol. 1997;75:326–334.[Medline] [Order article via Infotrieve]

110. Myers ML, Farhangkhoee P, Karmazyn M. Hydrogen peroxide induced impairment of post-ischemic ventricular function is prevented by the sodium-hydrogen exchange inhibitor HOE 642 (cariporide). Cardiovasc Res. 1998;40:290–296.[Abstract/Free Full Text]

111. Drexler H, Joachim H, Buerke M, Schultheiss H-P, von Daul J, Richardt G, Seyfarth M, Terres W, Sheehan FH. A Na⁺/H⁺ exchange inhibitor improves recovery of ventricular function in patients undergoing coronary angioplasty for acute anterior myocardial infarction. Circulation. 1998;98 (suppl I):I-344. Abstract.

112. Le Prigent K, Lagadic-Gossman D, Feuvray D. Modulation by pH_o and intracellular Ca²⁺ of Na⁺-H⁺ exchange in diabetic rat isolated ventricular myocytes. Circ Res. 1997;80:253–260.[Abstract/Free Full Text]

113. Kusuoka H, Matsuda S, Ishikawa M, Koga K, Mori T, Yamaguchi H, Nishimura T. Differences in the mechanisms for compensating ischemic acidosis in diabetic rat hearts. J Mol Cell Cardiol. 1998;30:1643–1649.[Medline] [Order article via Infotrieve]

114. Feuvray D. Response to ischemia and reperfusion by the diabetic heart. In: Karmazyn M, ed. Myocardial Ischemia: Mechanisms, Reperfusion, Protection. Basel, Switzerland: Birkhäuser; 1996:409–421.

115. Imahashi K, Hashimoto K, Yamaguchi H, Nishimura T, Kusuoka H. Alterations of intracellular Na⁺ during ischemia in diabetic rat heart hearts: the role of reduced activity in Na⁺/H⁺ exchange against stunning. J Mol Cell Cardiol. 1998;30:509–517.[Medline] [Order article via Infotrieve]

116. Kranzhöfer R, Schirmer J, Schömig A, von Hodenberg E, Pestel E, Metz J, Lang HJ, Kübler W. Suppression of neointimal thickening and smooth muscle cell proliferation after arterial injury in the rat by inhibitors of Na⁺-H⁺ exchange. Circ Res. 1993;73:264–268.[Abstract/Free Full Text]

117. Mitsuka M, Nagae M, Berk BC. Na⁺-H⁺ exchange inhibitors decrease neointimal formation after rat carotid injury: effects on smooth muscle cell migration and proliferation. Circ Res. 1993;73:269–275.[Abstract/Free Full Text]

118. Peiro C, Angulo J, Llergo JL, Rodriguez-Manas L, Marin J, Sanchez-Ferrer CF. Angiotensin II mediates cell hypertrophy in vascular smooth muscle cell cultures from hypertensive Ren-2 transgenic rats by an amiloride- and furosemide-sensitive mechanism. Biochem Biophys Res Commun. 1997;240:367–371.[Medline] [Order article via Infotrieve]

119. Yamazaki T, Komuro, I, Kudoh S, Zou Y, Nagai R, Aikawa R, Uozumi H, Yazaki Y. Role of ion channels and exchanger in mechanical stretch-induced cardiomyocyte hypertrophy. Circ Res. 1998;82:430–437.[Abstract/Free Full Text]

120. Cingolani HE, Alvarez BV, Ennis IL, Camillión de Hurtado MC. Stretch-induced alkalinization of feline papillary muscle: an autocrine-paracrine system. Circ Res. 1998;83:775–780.[Abstract/Free Full Text]

121. Hori M, Nakatsubo N, Kagiya T, Iwai K, Sato H, Iwakura K, Kitabatake A, Kamada T. The role of Na⁺/H⁺ exchange in norepinephrine-induced protein synthesis in neonatal cultured cardiomyocytes. Jpn Circ J. 1990;54:535–539.[Medline] [Order article via Infotrieve]

122. Hasegawa S, Nakano M, Taniguchi Y, Imai S, Murata K, Suzuki T. Effects of Na⁺-H⁺ exchange blocker amiloride on left ventricular remodeling after anterior myocardial infarction in rats. Cardiovasc Drugs Ther. 1995;9:823–826.[Medline] [Order article via Infotrieve]

123. Taniguchi Y, Nakano M, Hasegawa S, Kanda T, Imai S, Suzuki T, Kobayashi I, Nagai R. Beneficial effect of amiloride, a Na⁺-H⁺ exchange blocker, in a murine model of dilated cardiomyopathy. Res Commun Chem Pathol Pharmacol. 1996;92:201–210.

124. Yoshida H, Karmazyn M. Na⁺-H⁺ exchange inhibition attenuates hypertrophy and heart failure in one-week postinfarcted rat myocardium. Am J Physiol. In press.

125. Dostal DE, Baker KM. Angiotensin and endothelin: messengers that couple ventricular stretch to the Na⁺/H⁺ exchanger and cardiac hypertrophy. Circ Res. 1998;83:870–873.[Free Full Text]

126. Skolnick RL, Litwin SE, Barry WH, Spitzer KW. Effect of ANG II on pH_i, [Ca²⁺]_i, and contraction in rabbit ventricular myocytes from infarcted hearts. Am J Physiol. 1998;275:H1788–H1797.[Abstract/Free Full Text]

This article has been cited by other articles:

				M.A. H. Talukder, J. L. Zweier, and M. Periasamy Targeting calcium transport in ischaemic heart disease Cardiovasc Res, December 1, 2009; 84(3): 345 - 352. [Abstract] [Full Text] [PDF]

				C. D. L. Folmes, C. S. Wagg, M. Shen, A. S. Clanachan, R. Tian, and G. D. Lopaschuk Suppression of 5'-AMP-activated protein kinase activity does not impair recovery of contractile function during reperfusion of ischemic hearts Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H313 - H321. [Abstract] [Full Text] [PDF]

				S. E. McAllister, M. A. Moses, K. Jindal, H. Ashrafpour, N. J. Cahoon, N. Huang, P. C. Neligan, C. R. Forrest, J. E. Lipa, and C. Y. Pang Na+/H+ exchange inhibitor cariporide attenuates skeletal muscle infarction when administered before ischemia or reperfusion J Appl Physiol, January 1, 2009; 106(1): 20 - 28. [Abstract] [Full Text] [PDF]

				V. Prasad, I. Bodi, J. W. Meyer, Y. Wang, M. Ashraf, S. J. Engle, T. Doetschman, K. Sisco, M. L. Nieman, M. L. Miller, et al. Impaired Cardiac Contractility in Mice Lacking Both the AE3 Formula Exchanger and the NKCC1 Na+-K+-2Cl- Cotransporter: EFFECTS ON Ca2+ HANDLING AND PROTEIN PHOSPHATASES J. Biol. Chem., November 14, 2008; 283(46): 31303 - 31314. [Abstract] [Full Text] [PDF]

				T. Y. Nakamura, Y. Iwata, Y. Arai, K. Komamura, and S. Wakabayashi Activation of Na+/H+ Exchanger 1 Is Sufficient to Generate Ca2+ Signals That Induce Cardiac Hypertrophy and Heart Failure Circ. Res., October 10, 2008; 103(8): 891 - 899. [Abstract] [Full Text] [PDF]

				J. R. Schelling and B. G. Abu Jawdeh Regulation of cell survival by Na+/H+ exchanger-1 Am J Physiol Renal Physiol, September 1, 2008; 295(3): F625 - F632. [Abstract] [Full Text] [PDF]

				T. Doenst, H. Bugger, M. Schwarzer, G. Faerber, M. A. Borger, and F. W. Mohr Three good reasons for heart surgeons to understand cardiac metabolism Eur. J. Cardiothorac. Surg., May 1, 2008; 33(5): 862 - 871. [Abstract] [Full Text] [PDF]

				M. Kay, L. Swift, B. Martell, A. Arutunyan, and N. Sarvazyan Locations of ectopic beats coincide with spatial gradients of NADH in a regional model of low-flow reperfusion Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2400 - H2405. [Abstract] [Full Text] [PDF]

				R. M. Mentzer Jr, M. S. Jahania, and R. D. Lasley Myocardial Protection Card. Surg. Adult, January 1, 2008; 3(2008): 443 - 464. [Full Text]

				Y. Iwata, Y. Katanosaka, T. Hisamitsu, and S. Wakabayashi Enhanced Na+/H+ Exchange Activity Contributes to the Pathogenesis of Muscular Dystrophy via Involvement of P2 Receptors Am. J. Pathol., November 1, 2007; 171(5): 1576 - 1587. [Abstract] [Full Text] [PDF]

				T. Yamamoto, T. Shirayama, T. Sakatani, T. Takahashi, H. Tanaka, T. Takamatsu, K. W. Spitzer, and H. Matsubara Enhanced activity of ventricular Na+-HCO3 cotransport in pressure overload hypertrophy Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1254 - H1264. [Abstract] [Full Text] [PDF]

				M. T. Dirksen, G. J. Laarman, M. L. Simoons, and D. J.G.M. Duncker Reperfusion injury in humans: A review of clinical trials on reperfusion injury inhibitory strategies Cardiovasc Res, June 1, 2007; 74(3): 343 - 355. [Abstract] [Full Text] [PDF]

				K. Imahashi, F. Mraiche, C. Steenbergen, E. Murphy, and L. Fliegel Overexpression of the Na+/H+ exchanger and ischemia-reperfusion injury in the myocardium Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2237 - H2247. [Abstract] [Full Text] [PDF]

				N. G. Perez, M. R. Piaggio, I. L. Ennis, C. D. Garciarena, C. Morales, E. M. Escudero, O. H. Cingolani, G. Chiappe de Cingolani, X.-P. Yang, and H. E. Cingolani Phosphodiesterase 5A Inhibition Induces Na+/H+ Exchanger Blockade and Protection Against Myocardial Infarction Hypertension, May 1, 2007; 49(5): 1095 - 1103. [Abstract] [Full Text] [PDF]

				A. K. Snabaitis, R. D'Mello, S. Dashnyam, and M. Avkiran A Novel Role for Protein Phosphatase 2A in Receptor-mediated Regulation of the Cardiac Sarcolemmal Na+/H+ Exchanger NHE1 J. Biol. Chem., July 21, 2006; 281(29): 20252 - 20262. [Abstract] [Full Text] [PDF]

				C. Pott, D. Steinritz, B. Bolck, U. Mehlhorn, K. Brixius, R. H. G. Schwinger, and W. Bloch eNOS translocation but not eNOS phosphorylation is dependent on intracellular Ca2+ in human atrial myocardium Am J Physiol Cell Physiol, May 1, 2006; 290(5): C1437 - C1445. [Abstract] [Full Text] [PDF]

				N. Chai and P. Bates Na+/H+ exchanger type 1 is a receptor for pathogenic subgroup J avian leukosis virus PNAS, April 4, 2006; 103(14): 5531 - 5536. [Abstract] [Full Text] [PDF]

				N. S. Dhalla, M. R. Dent, P. S. Tappia, R. Sethi, J. Barta, and R. K. Goyal Subcellular Remodeling as a Viable Target for the Treatment of Congestive Heart Failure Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2006; 11(1): 31 - 45. [Abstract] [PDF]

				M. Yamamuro, M. Yoshimura, M. Nakayama, K. Abe, M. Shono, S. Suzuki, T. Sakamoto, Y. Saito, K. Nakao, H. Yasue, et al. Direct Effects of Aldosterone on Cardiomyocytes in the Presence of Normal and Elevated Extracellular Sodium Endocrinology, March 1, 2006; 147(3): 1314 - 1321. [Abstract] [Full Text] [PDF]

				A. Kilic, A. Velic, L. J. De Windt, L. Fabritz, M. Voss, D. Mitko, M. Zwiener, H. A. Baba, M. van Eickels, E. Schlatter, et al. Enhanced Activity of the Myocardial Na+/H+ Exchanger NHE-1 Contributes to Cardiac Remodeling in Atrial Natriuretic Peptide Receptor-Deficient Mice Circulation, October 11, 2005; 112(15): 2307 - 2317. [Abstract] [Full Text] [PDF]

				Q. Wang, A. A. Domenighetti, T. Pedrazzini, and M. Burnier Potassium Supplementation Reduces Cardiac and Renal Hypertrophy Independent of Blood Pressure in DOCA/Salt Mice Hypertension, September 1, 2005; 46(3): 547 - 554. [Abstract] [Full Text] [PDF]

				M. Dworschak, L. V. d'Uscio, D. Breukelmann, and J. D. Hannon Increased tolerance to hypoxic metabolic inhibition and reoxygenation of cardiomyocytes from apolipoprotein E-deficient mice Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H160 - H167. [Abstract] [Full Text] [PDF]

				Y. Yoshikawa, H. Hagihara, Y. Ohga, C. Nakajima-Takenaka, K.-y. Murata, S. Taniguchi, and M. Takaki Calpain inhibitor-1 protects the rat heart from ischemia-reperfusion injury: analysis by mechanical work and energetics Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1690 - H1698. [Abstract] [Full Text] [PDF]

				H. Hagihara, Y. Yoshikawa, Y. Ohga, C. Takenaka, K.-y. Murata, S. Taniguchi, and M. Takaki Na+/Ca2+ exchange inhibition protects the rat heart from ischemia-reperfusion injury by blocking energy-wasting processes Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1699 - H1707. [Abstract] [Full Text] [PDF]

				B. A. Watts III, T. George, and D. W. Good The Basolateral NHE1 Na+/H+ Exchanger Regulates Transepithelial HCO -3 Absorption through Actin Cytoskeleton Remodeling in Renal Thick Ascending Limb J. Biol. Chem., March 25, 2005; 280(12): 11439 - 11447. [Abstract] [Full Text] [PDF]

				T. Yamamoto, P. Swietach, A. Rossini, S.-H. Loh, R. D. Vaughan-Jones, and K. W. Spitzer Functional diversity of electrogenic Na+-HCO3- cotransport in ventricular myocytes from rat, rabbit and guinea pig J. Physiol., January 15, 2005; 562(2): 455 - 475. [Abstract] [Full Text] [PDF]

				M. A. Stagg and C. M.N. Terracciano Less Na+/H+-exchanger to treat heart failure: a simple solution for a complex problem? Cardiovasc Res, January 1, 2005; 65(1): 10 - 12. [Full Text] [PDF]

				M. Yeo, D.-K. Kim, Y.-B. Kim, T. Y. Oh, J.-E. Lee, S. W. Cho, H. C. Kim, and K.-B. Hahm Selective Induction of Apoptosis with Proton Pump Inhibitor in Gastric Cancer Cells Clin. Cancer Res., December 15, 2004; 10(24): 8687 - 8696. [Abstract] [Full Text] [PDF]

				S. Aker, A. K Snabaitis, I. Konietzka, A. van de Sand, K. Bongler, M. Avkiran, G. Heusch, and R. Schulz Inhibition of the Na+/H+ exchanger attenuates the deterioration of ventricular function during pacing-induced heart failure in rabbits Cardiovasc Res, August 1, 2004; 63(2): 273 - 282. [Abstract] [Full Text] [PDF]

				D. Fuster, O. W. Moe, and D. W. Hilgemann Lipid- and mechanosensitivities of sodium/hydrogen exchangers analyzed by electrical methods PNAS, July 13, 2004; 101(28): 10482 - 10487. [Abstract] [Full Text] [PDF]

				D. B. Kintner, G. Su, B. Lenart, A. J. Ballard, J. W. Meyer, L. L. Ng, G. E. Shull, and D. Sun Increased tolerance to oxygen and glucose deprivation in astrocytes from Na+/H+ exchanger isoform 1 null mice Am J Physiol Cell Physiol, July 1, 2004; 287(1): C12 - C21. [Abstract] [Full Text] [PDF]

				D. von Lewinski, B. Stumme, F. Fialka, C. Luers, and B. Pieske Functional Relevance of the Stretch-Dependent Slow Force Response in Failing Human Myocardium Circ. Res., May 28, 2004; 94(10): 1392 - 1398. [Abstract] [Full Text] [PDF]

				A. C. Reid, C. J. Mackins, N. Seyedi, R. Levi, and R. B. Silver Coupling of angiotensin II AT1 receptors to neuronal NHE activity and carrier-mediated norepinephrine release in myocardial ischemia Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1448 - H1454. [Abstract] [Full Text] [PDF]

				L. Chen, C. X. Chen, X. T. Gan, N. Beier, W. Scholz, and M. Karmazyn Inhibition and reversal of myocardial infarction-induced hypertrophy and heart failure by NHE-1 inhibition Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H381 - H387. [Abstract] [Full Text] [PDF]

				J. S. Corvera, Z.-Q. Zhao, L. S. Schmarkey, S. L. Katzmark, J. M. Budde, C. D. Morris, T. Ehring, R. A. Guyton, and J. Vinten-Johansen Optimal dose and mode of delivery of Na+/H+ exchange-1 inhibitor are critical for reducing postsurgical ischemia-reperfusion injury Ann. Thorac. Surg., November 1, 2003; 76(5): 1614 - 1622. [Abstract] [Full Text] [PDF]

				Y. Wang, J. W. Meyer, M. Ashraf, and G. E. Shull Mice With a Null Mutation in the NHE1 Na+-H+ Exchanger Are Resistant to Cardiac Ischemia-Reperfusion Injury Circ. Res., October 17, 2003; 93(8): 776 - 782. [Abstract] [Full Text] [PDF]

				J. E. Davies, S. B. Digerness, S. P. Goldberg, C. R. Killingsworth, C. R. Katholi, P. S. Brookes, and W. L. Holman Intra-myocyte ion homeostasis during ischemia-reperfusion injury: effects of pharmacologic preconditioning and controlled reperfusion Ann. Thorac. Surg., October 1, 2003; 76(4): 1252 - 1258. [Abstract] [Full Text] [PDF]

				M. Young and J. Funder Mineralocorticoid Action and Sodium-Hydrogen Exchange: Studies in Experimental Cardiac Fibrosis Endocrinology, September 1, 2003; 144(9): 3848 - 3851. [Abstract] [Full Text] [PDF]

				R. P Taylor, J. T Ciccolo, and J. W Starnes Effect of exercise training on the ability of the rat heart to tolerate hydrogen peroxide Cardiovasc Res, June 1, 2003; 58(3): 575 - 581. [Abstract] [Full Text] [PDF]

				I. M. Ayoub, J. Kolarova, Z. Yi, A. Trevedi, H. Deshmukh, D. L. Lubell, M. R. Franz, F. A. Maldonado, and R. J. Gazmuri Sodium-Hydrogen Exchange Inhibition During Ventricular Fibrillation: Beneficial Effects on Ischemic Contracture, Action Potential Duration, Reperfusion Arrhythmias, Myocardial Function, and Resuscitability Circulation, April 8, 2003; 107(13): 1804 - 1809. [Abstract] [Full Text] [PDF]

				S. B. Digerness, P. S. Brookes, S. P. Goldberg, C. R. Katholi, and W. L. Holman Modulation of mitochondrial adenosine triphosphate-sensitive potassium channels and sodium-hydrogen exchange provide additive protection from severe ischemia-reperfusion injury J. Thorac. Cardiovasc. Surg., April 1, 2003; 125(4): 863 - 871. [Abstract] [Full Text] [PDF]

				T. M. Kang, V. S. Markin, and D. W. Hilgemann Ion Fluxes in Giant Excised Cardiac Membrane Patches Detected and Quantified with Ion-selective Microelectrodes J. Gen. Physiol., March 31, 2003; 121(4): 325 - 348. [Abstract] [Full Text] [PDF]

				D. M Bers, W. H Barry, and S. Despa Intracellular Na+ regulation in cardiac myocytes Cardiovasc Res, March 15, 2003; 57(4): 897 - 912. [Abstract] [Full Text] [PDF]

				R. H.G Schwinger, H. Bundgaard, J. Muller-Ehmsen, and K. Kjeldsen The Na, K-ATPase in the failing human heart Cardiovasc Res, March 15, 2003; 57(4): 913 - 920. [Abstract] [Full Text] [PDF]

				D. G Allen and X.-H. Xiao Role of the cardiac Na+/H+ exchanger during ischemia and reperfusion Cardiovasc Res, March 15, 2003; 57(4): 934 - 941. [Abstract] [Full Text] [PDF]

				M. Avkiran and R. S Haworth Regulatory effects of G protein-coupled receptors on cardiac sarcolemmal Na+/H+ exchanger activity: signalling and significance Cardiovasc Res, March 15, 2003; 57(4): 942 - 952. [Abstract] [Full Text] [PDF]

				F. Verdonck, P. G.A Volders, M. A Vos, and K. R Sipido Increased Na+ concentration and altered Na/K pump activity in hypertrophied canine ventricular cells Cardiovasc Res, March 15, 2003; 57(4): 1035 - 1043. [Abstract] [Full Text] [PDF]

				D. von Lewinski, B. Stumme, L. S Maier, C. Luers, D. M Bers, and B. Pieske Stretch-dependent slow force response in isolated rabbit myocardium is Na+ dependent Cardiovasc Res, March 15, 2003; 57(4): 1052 - 1061. [Abstract] [Full Text] [PDF]

				J. V. Haist, C. N. Hirst, and M. Karmazyn Effective protection by NHE-1 inhibition in ischemic and reperfused heart under preconditioning blockade Am J Physiol Heart Circ Physiol, March 1, 2003; 284(3): H798 - H803. [Abstract] [Full Text] [PDF]

				W. P. Magee, G. Deshmukh, M. P. Deninno, J. C. Sutt, J. G. Chapman, and W. R. Tracey Differing cardioprotective efficacy of the Na+/Ca2+ exchanger inhibitors SEA0400 and KB-R7943 Am J Physiol Heart Circ Physiol, March 1, 2003; 284(3): H903 - H910. [Abstract] [Full Text] [PDF]

				G. Fujisawa, K. Okada, S. Muto, N. Fujita, N. Itabashi, E. Kusano, and S. Ishibashi Na/H Exchange Isoform 1 Is Involved in Mineralocorticoid/Salt-Induced Cardiac Injury Hypertension, March 1, 2003; 41(3): 493 - 498. [Abstract] [Full Text] [PDF]

				R. M. Mentzer Jr, R. D. Lasley, A. Jessel, and M. Karmazyn Intracellular sodium hydrogen exchange inhibition and clinical myocardial protection Ann. Thorac. Surg., February 1, 2003; 75(2): S700 - 708. [Abstract] [Full Text] [PDF]

				D. K. Das Attenuation of postischemic myocardial injury by cariporide J. Thorac. Cardiovasc. Surg., January 1, 2003; 125(1): 30 - 31. [Full Text] [PDF]

				R. M. Mentzer Jr., M. S. Jahania, and R. D. Lasley Myocardial Protection Card. Surg. Adult, January 1, 2003; 2(2003): 413 - 438. [Full Text]

				I. Szokodi, P. Tavi, G. Foldes, S. Voutilainen-Myllyla, M. Ilves, H. Tokola, S. Pikkarainen, J. Piuhola, J. Rysa, M. Toth, et al. Apelin, the Novel Endogenous Ligand of the Orphan Receptor APJ, Regulates Cardiac Contractility Circ. Res., September 6, 2002; 91(5): 434 - 440. [Abstract] [Full Text] [PDF]

				N. Nomura, H. Satoh, H. Terada, M. Matsunaga, H. Watanabe, and H. Hayashi CaMKII-dependent reactivation of SR Ca2+ uptake and contractile recovery during intracellular acidosis Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H193 - H203. [Abstract] [Full Text] [PDF]

				C. Sheldon and J. Church Intracellular pH Response to Anoxia in Acutely Dissociated Adult Rat Hippocampal CA1 Neurons J Neurophysiol, May 1, 2002; 87(5): 2209 - 2224. [Abstract] [Full Text] [PDF]

				K. Shinagawa, H. Mitamura, S. Ogawa, and S. Nattel Effects of inhibiting Na+/H+-exchange or angiotensin converting enzyme on atrial tachycardia-induced remodeling Cardiovasc Res, May 1, 2002; 54(2): 438 - 446. [Abstract] [Full Text] [PDF]

				S. Engelhardt, L. Hein, U. Keller, K. Klambt, and M. J. Lohse Inhibition of Na+-H+ Exchange Prevents Hypertrophy, Fibrosis, and Heart Failure in {beta}1-Adrenergic Receptor Transgenic Mice Circ. Res., April 19, 2002; 90(7): 814 - 819. [Abstract] [Full Text] [PDF]

				J. P. Loennechen, U. Wisloff, G. Falck, and O. Ellingsen Effects of Cariporide and Losartan on Hypertrophy, Calcium Transients, Contractility, and Gene Expression in Congestive Heart Failure Circulation, March 19, 2002; 105(11): 1380 - 1386. [Abstract] [Full Text] [PDF]

				M. Avkiran and M. S. Marber Na+/h+ exchange inhibitors for cardioprotective therapy: progress, problems and prospects J. Am. Coll. Cardiol., March 6, 2002; 39(5): 747 - 753. [Abstract] [Full Text] [PDF]

				S. P. Goldberg, S. B. Digerness, J. L. Skinner, C. R. Killingsworth, C. R. Katholi, and W. L. Holman Ischemic preconditioning and Na+/H+ exchange inhibition improve reperfusion ion homeostasis Ann. Thorac. Surg., February 1, 2002; 73(2): 569 - 574. [Abstract] [Full Text] [PDF]

				A. K Snabaitis, D. J Hearse, and M. Avkiran Regulation of sarcolemmal Na+/H+ exchange by hydrogen peroxide in adult rat ventricular myocytes Cardiovasc Res, February 1, 2002; 53(2): 470 - 480. [Abstract] [Full Text] [PDF]

				J. M.J Lamers Unmasking of a novel target for blocking harmful Na+ coupled acid extrusion: electrogenic Na+-HCO3- symport Cardiovasc Res, December 1, 2001; 52(3): 339 - 344. [Full Text] [PDF]

				N. Khandoudi, J. Albadine, P. Robert, S. Krief, I. Berrebi-Bertrand, X. Martin, M. O Bevensee, W. F Boron, and A. Bril Inhibition of the cardiac electrogenic sodium bicarbonate cotransporter reduces ischemic injury Cardiovasc Res, December 1, 2001; 52(3): 387 - 396. [Abstract] [Full Text] [PDF]

				U. Zeymer, H. Suryapranata, J. P. Monassier, G. Opolski, J. Davies, G. Rasmanis, G. Linssen, U. Tebbe, R. Schroder, R. Tiemann, et al. The Na+/H+ exchange inhibitor eniporide as an adjunct to early reperfusion therapy for acute myocardial infarction: Results of the evaluation of the safety and cardioprotective effects of eniporide in acute myocardial infarction (ESCAMI) trial J. Am. Coll. Cardiol., November 15, 2001; 38(6): 1644 - 1650. [Abstract] [Full Text] [PDF]

				S. Wei, E. C. Rothstein, L. Fliegel, L. J. Dell'Italia, and P. A. Lucchesi Differential MAP kinase activation and Na+/H+ exchanger phosphorylation by H2O2 in rat cardiac myocytes Am J Physiol Cell Physiol, November 1, 2001; 281(5): C1542 - C1550. [Abstract] [Full Text] [PDF]

				K. Sugishita, Z. Su, F. Li, K. D. Philipson, and W. H. Barry Gender Influences [Ca2+]i During Metabolic Inhibition in Myocytes Overexpressing the Na+-Ca2+ Exchanger Circulation, October 23, 2001; 104(17): 2101 - 2106. [Abstract] [Full Text] [PDF]

				Y. Toyoda, S. Khan, W. Chen, R. A. Parker, S. Levitsky, and J. D. McCully Effects of NHE-1 inhibition on cardioprotection and impact on protection by K/Mg cardioplegia Ann. Thorac. Surg., September 1, 2001; 72(3): 836 - 843. [Abstract] [Full Text] [PDF]

				L. Chen, X. T. Gan, J. V. Haist, Q. Feng, X. Lu, S. Chakrabarti, and M. Karmazyn Attenuation of Compensatory Right Ventricular Hypertrophy and Heart Failure following Monocrotaline-Induced Pulmonary Vascular Injury by the Na+-H+ Exchange Inhibitor Cariporide J. Pharmacol. Exp. Ther., August 1, 2001; 298(2): 469 - 476. [Abstract] [Full Text] [PDF]

				R. J. Gazmuri, I. M. Ayoub, E. Hoffner, and J. D. Kolarova Successful Ventricular Defibrillation by the Selective Sodium-Hydrogen Exchanger Isoform-1 Inhibitor Cariporide Circulation, July 10, 2001; 104(2): 234 - 239. [Abstract] [Full Text] [PDF]

				D. R. Knight, A. H. Smith, D. M. Flynn, J. T. MacAndrew, S. S. Ellery, J. X. Kong, R. B. Marala, R. T. Wester, A. Guzman-Perez, R. J. Hill, et al. A Novel Sodium-Hydrogen Exchanger Isoform-1 Inhibitor, Zoniporide, Reduces Ischemic Myocardial Injury in Vitro and in Vivo J. Pharmacol. Exp. Ther., April 1, 2001; 297(1): 254 - 259. [Abstract] [Full Text]

				M. Avkiran, G. Gross, M. Karmazyn, H. Klein, E. Murphy, and K. Ytrehus Na+/H+ exchange in ischemia, reperfusion and preconditioning Cardiovasc Res, April 1, 2001; 50(1): 162 - 163. [Full Text] [PDF]

				D. G Allen and X.-h. Xiao Na+ entry during ischemia, reperfusion and preconditioning Cardiovasc Res, April 1, 2001; 50(1): 164 - 166. [Full Text] [PDF]

				R. B. Silver, C. J. Mackins, N. C. E. Smith, I. L. Koritchneva, K. Lefkowitz, T. W. Lovenberg, and R. Levi Coupling of histamine H3 receptors to neuronal Na+/H+ exchange: A novel protective mechanism in myocardial ischemia PNAS, February 15, 2001; (2001) 51599198. [Abstract] [Full Text]

				K. Kusumoto, J. V. Haist, and M. Karmazyn Na+/H+ exchange inhibition reduces hypertrophy and heart failure after myocardial infarction in rats Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H738 - H745. [Abstract] [Full Text] [PDF]

				X-H. Xiao and D.G. Allen Activity of the Na+/H+ exchanger is critical to reperfusion damage and preconditioning in the isolated rat heart Cardiovasc Res, November 1, 2000; 48(2): 244 - 253. [Abstract] [Full Text] [PDF]

				H. Yokoyama, S. Gunasegaram, S. E. Harding, and M. Avkiran Sarcolemmal Na+/H+ exchanger activity and expression in human ventricular myocardium J. Am. Coll. Cardiol., August 1, 2000; 36(2): 534 - 540. [Abstract] [Full Text] [PDF]

				C. Ruwhof and A. van der Laarse Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways Cardiovasc Res, July 1, 2000; 47(1): 23 - 37. [Abstract] [Full Text] [PDF]

				H. Yoshida and M. Karmazyn Na+/H+ exchange inhibition attenuates hypertrophy and heart failure in 1-wk postinfarction rat myocardium Am J Physiol Heart Circ Physiol, January 1, 2000; 278(1): H300 - H304. [Abstract] [Full Text] [PDF]

				A. N. Moor, X. T. Gan, M. Karmazyn, and L. Fliegel Activation of Na+/H+ Exchanger-directed Protein Kinases in the Ischemic and Ischemic-reperfused Rat Myocardium J. Biol. Chem., May 4, 2001; 276(19): 16113 - 16122. [Abstract] [Full Text] [PDF]

				R. B. Silver, C. J. Mackins, N. C. E. Smith, I. L. Koritchneva, K. Lefkowitz, T. W. Lovenberg, and R. Levi Coupling of histamine H3 receptors to neuronal Na+/H+ exchange: A novel protective mechanism in myocardial ischemia PNAS, February 27, 2001; 98(5): 2855 - 2859. [Abstract] [Full Text] [PDF]

				K. Imahashi, T. Nishimura, J. Yoshioka, and H. Kusuoka Role of Intracellular Na+ Kinetics in Preconditioned Rat Heart Circ. Res., June 8, 2001; 88(11): 1176 - 1182. [Abstract] [Full Text] [PDF]

				M. G. Vila Petroff, J. M. Egan, X. Wang, and S. J. Sollott Glucagon-Like Peptide-1 Increases cAMP but Fails to Augment Contraction in Adult Rat Cardiac Myocytes Circ. Res., August 31, 2001; 89(5): 445 - 452. [Abstract] [Full Text] [PDF]

				B. V. Alvarez, J. Fujinaga, and J. R. Casey Molecular Basis for Angiotensin II-Induced Increase of Chloride/Bicarbonate Exchange in the Myocardium Circ. Res., December 7, 2001; 89(12): 1246 - 1253. [Abstract] [Full Text] [PDF]

				S. Engelhardt, L. Hein, U. Keller, K. Klambt, and M. J. Lohse Inhibition of Na+-H+ Exchange Prevents Hypertrophy, Fibrosis, and Heart Failure in {beta}1-Adrenergic Receptor Transgenic Mice Circ. Res., April 19, 2002; 90(7): 814 - 819. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Karmazyn, M. Articles by Kusumoto, K. Search for Related Content PubMed PubMed Citation Articles by Karmazyn, M. Articles by Kusumoto, K. Related Collections Ischemic biology - basic studies Ion channels/membrane transport