Successful ventricular defibrillation by the selective sodium-hydrogen exchanger isoform-1 inhibitor cariporide.
BACKGROUND
Sodium-hydrogen exchanger isoform-1 (NHE-1) activation worsens functional myocardial abnormalities associated with ischemia and reperfusion. We hypothesize that these abnormalities may limit cardiac resuscitation from ventricular fibrillation (VF) and investigated whether NHE-1 inhibition with the benzoylguanidine derivative cariporide could improve resuscitability, postresuscitation myocardial function, and short-term survival in isolated heart and intact rat models of VF. Methods and Results-- In the isolated rat heart, VF was induced for 25 minutes. Perfusion was interrupted for the initial 10 minutes and restarted at 10% of baseline flow for the remaining 15 minutes (simulating chest compression). Cariporide ameliorated ischemic contracture, prevented postresuscitation diastolic dysfunction, and favored earlier return of contractile function. In the intact rat, cariporide, injected into the right atrium before chest compression was started (after 6 minutes of untreated VF), prompted spontaneous defibrillation between minutes 7 and 9 of chest compression in 6 of 8 rats. In contrast, electrical defibrillation was required in each of 8 control rats after completion of a predetermined 16-minute interval of VF. After resuscitation, cariporide-treated rats had less ventricular ectopic activity and normalized their hemodynamic function faster. Electrical defibrillation was then timed in control rats to match the time when spontaneous defibrillation occurred in cariporide-treated rats. With comparable VF duration, postresuscitation hemodynamic dysfunction was ameliorated by cariporide, but only when more severe ischemia was modeled by prolongation of the interval of untreated VF from 6 to 10 minutes.


CONCLUSIONS
NHE-1 inhibition may represent a novel and remarkably effective intervention for resuscitation from VF.
Gazmuri
R J
RJ
Medical Service, Section of Critical Care Medicine, North Chicago VA Medical Center, Chicago, IL 60064, USA. raul.gazmuri@med.va.gov
Ayoub
I M
IM
Hoffner
E
E
Kolarova
J D
JD
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D016887:Cardiopulmonary Resuscitation; D004195:Disease Models, Animal; D004554:Electric Countershock; D006146:Guanidines / Q000494:pharmacology*; D006352:Heart Ventricles / Q000187:drug effects* / Q000503:physiopathology; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000097:blood; D051381:Rats; D012044:Regression Analysis; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology*; D015996:Survival Rate; D014693:Ventricular Fibrillation / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D018879:Ventricular Premature Complexes / Q000188:drug therapy / Q000209:etiology
D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C069139:growth factor-activatable Na-H exchanger NHE-1; D019344:Lactic Acid; C093373:cariporide