IMR Press / RCM / Volume 23 / Issue 8 / DOI: 10.31083/j.rcm2308284
Open Access Review
The Remaining Conundrum of the Role of the Na+/H+ Exchanger Isoform 1 (NHE1) in Cardiac Physiology and Pathology: Can It Be Rectified?
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1 Department of Physiology and Pharmacology, University of Western Ontario, London, ON N6A 5C1, Canada
2 Institute of Cardiovascular Sciences, Albrechtsen Research Centre, St. Boniface Hospital, and Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R2H 2A6, Canada
3 Department of Biochemistry, University Alberta, Edmonton, AB T6G 2H7, Canada
*Correspondence: (Larry Fliegel)
Academic Editor: Fabian Sanchis-Gomar
Rev. Cardiovasc. Med. 2022, 23(8), 284;
Submitted: 8 June 2022 | Revised: 29 June 2022 | Accepted: 8 July 2022 | Published: 15 August 2022
(This article belongs to the Special Issue Highlighting Excellence in Cardiovascular Research in Canada)
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.

The mammalian Na+/H+ exchanger (NHE) is a family of ubiquitous membrane proteins present in humans. Isoform one (NHE1) is present on the plasma membrane and regulates intracellular pH by removal of one intracellular proton in exchange for one extracellular sodium thus functioning as an electroneutral process. Human NHE1 has a 500 amino acid membrane domain plus a C-terminal 315 amino acid, regulatory cytosolic tail. It is regulated through a cytosolic regulatory C-terminal tail which is subject to phosphorylation and is modulated by proteins and lipids. Substantial evidence has implicated NHE1 activity in both myocardial ischemia and reperfusion damage and myocardial remodeling resulting in heart failure. Experimental data show excellent cardioprotection with NHE1 inhibitors although results from clinical results have been mixed. In cardiac surgery patients receiving the NHE1 inhibitor cariporide, subgroups showed beneficial effects of treatment. However, in one trial this was associated with a significantly increased incidence of ischemic strokes. This likely reflected both inappropriate dosing regimens as well as overly high drug doses. We suggest that further progress towards NHE1 inhibition as a treatment for cardiovascular disease is warranted through the development of novel compounds to inhibit NHE1 that are structurally different than those previously used in compromised clinical trials. Some novel pyrazinoyl guanidine inhibitors of NHE1 are already in development and the recent elucidation of the three-dimensional structure of the NHE1 protein and identity of the inhibitor binding site may facilitate development. An alternative approach may also be to control the endogenous regulation of activity of NHE1, which is activated in disease.

NHE1 regulation
NHE1 inhibitors
cardiac hypertrophy and remodelling
ischemia/reperfusion injury
pyrazinoyl guanidine
MOP 97816/Canadian Institutes of Health Research
Fig. 1.
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