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. doi: 10.1161/01.CIR.0000058704.45646.0D. Epub 2003 Mar 24.


Background: Inhibition of the sarcolemmal sodium-hydrogen exchanger isoform-1 (NHE-1) is emerging as a promising novel strategy for ameliorating myocardial injury associated with ischemia and reperfusion. We investigated whether NHE-1 inhibition (with cariporide) could minimize mechanical and electrical myocardial abnormalities that develop during ventricular fibrillation (VF) and improve outcome using a porcine model of closed-chest resuscitation.

Methods and results: Two groups of 8 pigs each were subjected to 8 minutes of untreated VF and randomized to receive either a 3-mg/kg bolus of cariporide or 0.9% NaCl immediately before an 8-minute interval of conventional closed-chest resuscitation. Cariporide prevented progressive increases in left ventricular free-wall thickness (from 1.0+/-0.2 to 1.5+/-0.3 cm with NaCl, P<0.001 versus 0.9+/-0.1 to 1.1+/-0.3 cm with cariporide, P=NS), maintained the coronary perfusion pressure above resuscitability thresholds (10+/-8 versus 19+/-3 mm Hg before attempting defibrillation, P<0.05), and increased resuscitability (2 of 8 versus 8 of 8, P<0.005). In 2 additional groups of 4 pigs each subjected to a briefer interval of untreated VF, cariporide ameliorated postresuscitation shortening of the action potential duration (APD) at 30%, 60%, and 90% repolarization (ie, APD60 at 2 minutes after resuscitation; 75+/-29 versus 226+/-16 ms, P<0.05), minimized postresuscitation ventricular ectopic activity preventing recurrent VF, and lessened postresuscitation myocardial dysfunction.

Conclusions: NHE-1 inhibition may represent a highly potent novel strategy for resuscitation from VF that can ameliorate myocardial manifestations of ischemic injury and improve the effectiveness and outcome of closed-chest resuscitation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Anti-Arrhythmia Agents / therapeutic use
  • Arrhythmias, Cardiac / etiology
  • Arrhythmias, Cardiac / pathology
  • Arrhythmias, Cardiac / physiopathology
  • Arrhythmias, Cardiac / prevention & control*
  • Combined Modality Therapy
  • Echocardiography, Transesophageal
  • Guanidines / therapeutic use
  • Heart / physiopathology
  • Male
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / physiopathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Resuscitation*
  • Secondary Prevention
  • Sodium-Hydrogen Exchangers / antagonists & inhibitors*
  • Sulfones / therapeutic use
  • Swine
  • Ventricular Fibrillation / diagnostic imaging
  • Ventricular Fibrillation / drug therapy
  • Ventricular Fibrillation / physiopathology
  • Ventricular Fibrillation / therapy*
  • Ventricular Function, Left


  • Anti-Arrhythmia Agents
  • Guanidines
  • Sodium-Hydrogen Exchangers
  • Sulfones
  • growth factor-activatable Na-H exchanger NHE-1
  • cariporide