AVE4454B--a novel sodium-hydrogen exchanger isoform-1 inhibitor--compared less effective than cariporide for resuscitation from cardiac arrest.
We compared the efficacy of the novel sodium-hydrogen exchanger (NHE-1) inhibitor AVE4454B with cariporide for resuscitation from ventricular fibrillation (VF) assessing the effects on left ventricular myocardial distensibility during chest compression, myocardial function after the return of spontaneous circulation, and survival. Three groups of 10 rats each were subjected to 10 min of untreated VF and resuscitation attempted by providing chest compression for up to 8 min with the depth of compression adjusted to attain an aortic diastolic pressure between 26 and 28 mmHg (to secure a coronary perfusion pressure above 20 mmHg) followed by electrical shocks. Rats received AVE4454B (1 mg/kg), cariporide (1 mg/kg), or vehicle control immediately before chest compression. We observed that NHE-1 inhibition (NHEI) preserved left ventricular myocardial distensibility during chest compression evidenced by less depth of compression required to attain the target aortic diastolic pressure corresponding to (mean ± standard deviation) 14.1 ± 1.1 mm in the AVE4454B group (P < 0.001 versus control), 15.0 ± 1.4 mm in the cariporide group (P < 0.01 versus control), and 17.0 ± 1.2 mm in controls. When the depth of compression was related to the coronary perfusion pressure generated-an index of left ventricular distensibility-only the cariporide group attained statistical significance. Postresuscitation, both compounds ameliorated myocardial dysfunction evidenced by lesser reductions in mean aortic pressure and the maximal rate of left ventricular pressure increase as well as earlier normalization of left ventricular end-diastolic pressure increases. This effect was associated with improved survival corresponding to 55% in the AVE4454B group (not significant) and 70% in the cariporide group (P < 0.01 versus control by Gehan-Breslow analysis) at 240 min postresuscitation. An inverse correlation was found between plasma cytochrome c and indices of left ventricular function at 240 min postresuscitation suggesting that NHEI exerts beneficial effects in part by attenuating mitochondrial injury. We conclude that cariporide is more effective than AVE4454B for resuscitation from cardiac arrest given its more prominent effect on preserving left ventricular myocardial distensibility and promoting survival.
Resuscitation Institute at Rosalind Franklin University of Medicine and Science and Medical Service, Section of Critical Care Medicine, Captain James A. Lovell Federal Health Care Center, North Chicago, Ill 60064, USA.
Jeejabai
J
Radhakrishnan
Julieta D
JD
Kolarova
Iyad M
IM
Ayoub
Raúl J
RJ
Gazmuri
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use*; D006323:Heart Arrest / Q000188:drug therapy*; D020128:Inhibitory Concentration 50; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use*; D014693:Ventricular Fibrillation / Q000188:drug therapy; D016277:Ventricular Function, Left / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide
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