Role of NHE1 in the Cellular Dysfunction of Acute Metabolic Acidosis

Abstract

Background: Metabolic acidosis is associated with impaired cellular function. This has been attributed to the accompanying reduction in intracellular and interstitial pH of the myocardium. Recent studies suggest that activation of the cellular Na⁺-H⁺ exchanger NHE1 might contribute to myocardial dysfunction. This review examines the experimental evidence which supports the role of NHE1 in the genesis of acidosis-induced cellular dysfunction, the benefits of its inhibition, and the type of acidosis that might benefit from therapy. Summary: Information was obtained by searching MEDLINE for articles published between 1969 and 2013 using the terms: NHE1, metabolic acidosis, lactic acidosis, ischemia-reperfusion, shock, resuscitation, high anion gap acidosis, and non-gap acidosis. Each article was also reviewed for additional suitable references. Nineteen manuscripts published between 2002 and 2013 assessed the impact of inhibition of NHE1 on cellular function. They revealed that NHE1 is activated with metabolic acidosis associated with hypoxia, hypoperfusion, hemorrhagic shock, and sepsis. This was associated with a rise in cellular sodium and calcium and cardiac dysfunction including reduced contractility and a predisposition to cardiac arrhythmias. Inhibition of NHE1 with specific inhibitors improved cardiac function, reduced blood and tissue levels of proinflammatory cytokines, and decreased mortality. Key Message: These results suggest that use of inhibitors of NHE1 might be worthwhile in the treatment of some types of acute metabolic acidosis, specifically the lactic acidosis associated with hypoxia, hemorrhagic shock, and cardiac arrest. Its potential role in the treatment of other forms of acute metabolic acidosis remains to be determined.

Lactic Acidosis: Current Treatments and Future Directions

“…55 Administration of selective inhibitors of NHE1 to experimental animals with lactic acidosis due to severe volume depletion, sepsis, or trauma improved cardiac function, reduced inflammation, ameliorated lactic acidosis, and decreased mortality. 56 The injurious cellular effects of NHE1 activation in these models are presumed to emanate from the resulting sodium influx that cannot be countered by the suppressed Na 1 /K 1 -ATPase activity consequent to hypoxia-induced ATP depletion. If generation of lactic acidosis is largely driven by aerobic glycolysis, the prevailing b 2 -stimulation of Na 1 /K 1 -ATPase activity might prevent sodium overload, thereby eliminating the indication for NHE1 inhibition.…”

Cancer cell behaviors mediated by dysregulated pH dynamics at a glance

“…The activity of these transporters is regulated not only by changes in pH i as a homeostatic mechanism but also by intra-or extra-cellular cues, such as oncogenes (GrilloHill et al, 2015;Reshkin et al, 2014), growth factor signaling (Counillon and Pouyssegur, 1995;Clement et al, 2013;Meima et al, 2009;Counillon et al, 2016), metabolic burden (Odunewu and Fliegel, 2013;Wu and Kraut, 2014), hypoxia and osmolarity (Lacroix et al, 2008;Counillon et al, 2016). In cancer cells, pH i is increased compared to normal cells (∼7.3-7.6 versus ∼7.2), while extracellular pH ( pH e ) is decreased (∼6.8-7.0 versus ∼7.4; see poster).…”

Treatment of Acidified Blood Using Reduced Osmolarity Mixed-Base Solutions

“…Also, the normal pH-regulatory proteins, including the Na + -H + exchanger, NHE1, will tend to improve cellular acid-base balance even in the absence of administered base restoring cellular pH to baseline. However, activation of this transporter can cause deleterious increments in cellular sodium and calcium and typically needs to be minimized (Wu and Kraut, 2014). Thus, there are likely to be some situations in which administration of simple bicarbonate solutions might be sufficient without requiring the properties of a ROMB solution that contains a high proportion of a strong base.…”