NHE-1 and NHE-6 Activities

Abstract

T he study 1 published in this issue of Circulation Research showing that a null mutation of NHE-1 improves the tolerance of the heart to ischemia and reperfusion (I/R) is an important contribution for the following reasons: (1) In the animals with null mutation, contracture during the ischemic period was less and ATP levels were preserved compared with wild-type animals. This observation, on the one hand, provides evidence that protection by downregulation of NHE-1 during the ischemic period itself is indeed possible and, on the other hand, it argues against the suggestion that the exchanger is inactive during this same period. 2 (2) In contrast with chronic blockade of the NHE-1 by pharmacological interventions, 3 the long-term absence of the exchanger does not elicit major compensatory changes that, in turn, might negate the cardioprotective effect of blocking its activity for a relative short term. This point is related to a recent publication 3 showing that long-term treatment with the NHE-1 blocker cariporide is followed by an upregulation of the functional units of the exchanger in a similar way to the well-known tolerance phenomenon following ␤-adrenergic receptor blockade. The absence of such upregulation negates possible hypersensitivity to ischemia upon withdrawal of the medication. The risk is evident in hearts with upregulation of NHE-1, which gain Na ϩ i more rapidly during ischemia, and show impaired recovery after reperfusion. 4 (3) No additional protection was obtained by adding the NHE-1 blocker eniporide to the NHE-1 null mice, suggesting that there is not another NHE isoform that can be blocked with this compound to add additional protection; the findings additionally hint that the attenuation of the injury obtained by the absence of the sarcolemmal NHE

Mechanisms of cardiodepression by an Na+–H+exchange inhibitor methyl-N-isobutyl amiloride (MIA) on the heart: lack of beneficial effects in ischemia–reperfusion injuryThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigators' Forum.

“…Since NHE is also known to be present on the inner mitochondrial membrane (Numata et al 1998) and different NHE inhibitors have been shown to depress the mitochondrial NHE (Cingolani et al 2003), it is likely that mitochondrial function is affected in presence of MIA. It was interesting to note that MIA treatment had no direct effect on mitochondrial respiration or oxidative phosphorylation; however, basal mitochondrial Ca 2+ concentration and Ca 2+ uptake by mitochondria were significantly augmented by treatment with MIA.…”

Protective effect of vitamin B6 against doxorubicin‐induced cardiotoxicity by modulating NHE1 expression

“…The Na + /H + exchanger isoform 1 (NHE1 [SLC9A1]) is the main subtype of membrane proteins that mediate the exchange of one intracellular H + for one extracellular Na + , thereby regulating intracellular pH and cell volume, [21,22] which presented predominantly in the myocardium [23] and is associated with oxidative stress and apoptosis. [24,25] NHE1 is the most abundant subtype of the NHE1 family, and it is expressed in a wide range of tissues, including the heart, kidneys, brain, and gastrointestinal tract. Chronic inhibition of NHE1 reduces heart failure [26][27][28][29] and reduces the production of reactive oxygen species (ROS).…”

The RSK Inhibitor BIX02565 Limits Cardiac Ischemia/Reperfusion Injury

“…Under conditions of low oxygen supply (which occurs during ischemia/reperfusion [I/R] injury), transporters such as the sodium–hydrogen exchanger (NHE) are important regulators of pHi. 1-3 The NHE1 is the major isoform expressed in heart 3 pharmacologic or genetic inhibition of NHE1 activity and has been proven to protect mouse hearts from I/R injury. 4-7 However, clinical trials using NHE1 in humans showed mixed results and side effects.…”