Abstract 48: AVE4454 (a New NHE-1 Inhibitor) Administered During Resuscitation from VF Ameliorates Post-Resuscitation Myocardial Dysfunction
Introduction: We have previously reported that cariporide, a selective NHE-1 inhibitor, ameliorates myocardial abnormalities associated with resuscitation from ventricular fibrillation (VF). Cariporide, however, failed clinical trials due to adverse neurological effects unrelated to the mode of action.
Hypothesis: We investigated in a rat model of VF and closed-chest resuscitation whether administration of the newly developed NHE-1 inhibitor AVE4454 can replicate the beneficial effects of cariporide during resuscitation from VF.
Methods: Thirty rats underwent 10 mins of untreated VF followed by 8 mins of chest compression before attempting defibrillation. Rats were randomized to received a right atrial bolus of cariporide (1 mg/kg, n = 10), AVE4454 (1 mg/kg, n = 10), or equivalent amounts of vehicle (n = 10) immediately before starting chest compression.
Results: Both NHE-1 inhibitors decreased the depth of compression between minutes 5 and 8 of chest compression (data not shown). Administration of cariporide and AVE4454 was associated with higher mean aortic pressure than control [94 ± 13 (p < 0.02) and 99 ± 11 (p < 0.05) vs 77 ± 15 mmHg], and higher left ventricular stroke work index [0.31 ± 0.1 (p = 0.46) and 0.43 ± 0.12 (p < 0.02) vs 0.27 ± 0.08 gm-m/kg/beat] at 30 minutes post-resuscitation and numerically better survival compared to controls (Figure⇓).
Conclusions: In our intact rat model of VF and closed-chest resuscitation AVE4454 was as effective as cariporide in ameliorating ischemic contracture and post-resuscitation myocardial dysfunction with less prominent effects on short-term survival.