NHE-1 INHIBITORS

– Preclinical Development –

The sodium-hydrogen exchanger isoform1 (NHE-1) is an exchanger of sodium and hydrogen ions ubiquitously expressed in the cell membrane of cells throughout the body (left figure). It is activated in the heart muscle after cardiac arrest occurs consequent to the intense intracellular acidosis that accompanies ischemia1. Sodium enters the cell in exchange for hydrogen ions and accumulates in the cytosol prompting calcium entry through reverse mode operation of the sodium-calcium exchanger. The resulting sodium-driven calcium overload causes among other effects mitochondrial injury intensifying damage to the heart muscle (right figure).
We have reported in animal models consistent beneficial myocardial effects of NHE-1 inhibitors given during cardiac resuscitation,2-14 associated with attenuation of sodium-driven calcium overload3,11 and preservation of mitochondrial bioenergetic function10. The effects include preservation of left ventricular distensibility3,5,10,12 enabling hemodynamically more effective chest compressions,2,5,8,9 return of cardiac activity with greater electrical stability,2,5-7 better post-resuscitation myocardial function,3,5,7,10,12,14 and attenuation of adverse myocardial effects of epinephrine,7 all contributing to better post-resuscitation hemodynamic function and survival.4,5,13,14

Related Publications:

  1. Gazmuri RJ, Radhakrishnan J, Ayoub IM. Sodium-Hydrogen Exchanger Isoform-1 Inhibition: A Promising Pharmacological Intervention for Resuscitation from Cardiac Arrest. Molecules. 2019 May 7;24(9):1765.
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  1. Gazmuri RJ, Ayoub IM, Hoffner E, Kolarova JD. Successful ventricular defibrillation by the selective sodium-hydrogen exchanger isoform-1 inhibitor cariporide. Circulation. 2001 Jul 10;104(2):234-9.
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  1. Gazmuri RJ, Hoffner E, Kalcheim J, Ho H, Patel M, Ayoub IM, Epstein M, Kingston S, Han Y. Myocardial protection during ventricular fibrillation by reduction of proton-driven sarcolemmal sodium influx. J Lab Clin Med. 2001 Jan;137(1):43-55.
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  1. Gazmuri RJ, Ayoub IM, Kolarova JD, Karmazyn M. Myocardial protection during ventricular fibrillation by inhibition of the sodium-hydrogen exchanger isoform-1. Crit Care Med. 2002 Apr;30(4 Suppl):S166-71.
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  1. Ayoub IM, Kolarova J, Yi Z, Trevedi A, Deshmukh H, Lubell DL, Franz MR, Maldonado FA, Gazmuri RJ. Sodium-hydrogen exchange inhibition during ventricular fibrillation: Beneficial effects on ischemic contracture, action potential duration, reperfusion arrhythmias, myocardial function, and resuscitability. Circulation. 2003 Apr 8;107(13):1804-9.
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  1. Kolarova J, Ayoub IM, Yi Z, Gazmuri RJ. Optimal timing for electrical defibrillation after prolonged untreated ventricular fibrillation. Crit Care Med. 2003 Jul;31(7):2022-8.
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  1. Ayoub IM, Kolarova J, Kantola RL, Sanders R, Gazmuri RJ. Cariporide minimizes adverse myocardial effects of epinephrine during resuscitation from ventricular fibrillation. Crit Care Med. 2005 Nov;33(11):2599-605.
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  1. Kolarova JD, Ayoub IM, Gazmuri RJ. Cariporide enables hemodynamically more effective chest compression by leftward shift of its flow-depth relationship. Am J Physiol Heart Circ Physiol. 2005 Jun;288(6):H2904-11.
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  1. Kolarova J, Yi Z, Ayoub IM, Gazmuri RJ. Cariporide potentiates the effects of epinephrine and vasopressin by nonvascular mechanisms during closed-chest resuscitation. Chest. 2005 Apr;127(4):1327-34.
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  1. Ayoub IM, Kolarova JD, Kantola RL, Radhakrishnan J, Wang S, Gazmuri RJ. Zoniporide preserves left ventricular compliance during ventricular fibrillation and minimizes postresuscitation myocardial dysfunction through benefits on energy metabolism. Crit Care Med. 2007 Oct;35(10):2329-36.
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  1. Wang S, Radhakrishnan J, Ayoub IM, Kolarova JD, Taglieri DM, Gazmuri RJ. Limiting sarcolemmal Na+ entry during resuscitation from ventricular fibrillation prevents excess mitochondrial Ca2+ accumulation and attenuates myocardial injury. J Appl Physiol (1985). 2007 Jul;103(1):55-65.
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  1. Ayoub IM, Kolarova J, Gazmuri RJ. Cariporide given during resuscitation promotes return of electrically stable and mechanically competent cardiac activity. Resuscitation. 2010 Jan;81(1):106-10.
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  1. Radhakrishnan J, Kolarova JD, Ayoub IM, Gazmuri RJ. AVE4454B–a novel sodium-hydrogen exchanger isoform-1 inhibitor–compared less effective than cariporide for resuscitation from cardiac arrest. Transl Res. 2011 Feb;157(2):71-80.
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  2. Lamoureux L, Radhakrishnan J, Mason TG, Kraut JA, Gazmuri RJ. Adverse postresuscitation myocardial effects elicited by buffer-induced alkalemia ameliorated by NHE-1 inhibition in a rat model of ventricular fibrillation. J Appl Physiol (1985). 2016 Nov 1;121(5):1160-1168.
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We have completed the preclinical research phase and are in the planning phase of clinical development. Stay tuned…