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Sodium-Hydrogen Exchanger Isoform-1 Inhibition: A Promising Pharmacological Intervention for Resuscitation from Cardiac Arrest

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Resuscitation Institute, Rosalind Franklin University of Medicine and Science, Section of Critical Care Medicine, Captain James A. Lovell Federal Health Care Center, North Chicago, IL 60064, USA
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Resuscitation Institute, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Morris Karmazyn
Molecules 2019, 24(9), 1765; https://doi.org/10.3390/molecules24091765
Received: 2 April 2019 / Accepted: 23 April 2019 / Published: 7 May 2019
(This article belongs to the Special Issue Cardiovascular Diseases Prevention and Therapy)
Out-of-hospital sudden cardiac arrest is a major public health problem with an overall survival of less than 5%. Upon cardiac arrest, cessation of coronary blood flow rapidly leads to intense myocardial ischemia and activation of the sarcolemmal Na+-H+ exchanger isoform-1 (NHE-1). NHE-1 activation drives Na+ into cardiomyocytes in exchange for H+ with its exchange rate intensified upon reperfusion during the resuscitation effort. Na+ accumulates in the cytosol driving Ca2+ entry through the Na+-Ca2+ exchanger, eventually causing cytosolic and mitochondrial Ca2+ overload and worsening myocardial injury by compromising mitochondrial bioenergetic function. We have reported clinically relevant myocardial effects elicited by NHE-1 inhibitors given during resuscitation in animal models of ventricular fibrillation (VF). These effects include: (a) preservation of left ventricular distensibility enabling hemodynamically more effective chest compressions, (b) return of cardiac activity with greater electrical stability reducing post-resuscitation episodes of VF, (c) less post-resuscitation myocardial dysfunction, and (d) attenuation of adverse myocardial effects of epinephrine; all contributing to improved survival in animal models. Mechanistically, NHE-1 inhibition reduces adverse effects stemming from Na+–driven cytosolic and mitochondrial Ca2+ overload. We believe the preclinical work herein discussed provides a persuasive rationale for examining the potential role of NHE-1 inhibitors for cardiac resuscitation in humans. View Full-Text
Keywords: cardiopulmonary resuscitation; energy metabolism; ischemia; mitochondria; myocardium; reperfusion injury; sodium calcium exchanger; sudden cardiac arrest; ventricular function cardiopulmonary resuscitation; energy metabolism; ischemia; mitochondria; myocardium; reperfusion injury; sodium calcium exchanger; sudden cardiac arrest; ventricular function
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Gazmuri, R.J.; Radhakrishnan, J.; Ayoub, I.M. Sodium-Hydrogen Exchanger Isoform-1 Inhibition: A Promising Pharmacological Intervention for Resuscitation from Cardiac Arrest. Molecules 2019, 24, 1765.

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