AVE4454B--a novel sodium-hydrogen exchanger isoform-1 inhibitor--compared less effective than cariporide for resuscitation from cardiac arrest

Abstract

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.

Copyright © 2011 Mosby, Inc. All rights reserved.

Figures

Figure 1

The depth of chest compression (Depth) and ratio between coronary perfusion pressure and depth of compression (CPP/Depth) are shown in rats that received vehicle control solution (C), the NHE-1 inhibitor AVE4454B (AVE), or cariporide (CRP) just before starting chest compression. NHEI = AVE and CRP groups combined. The line graphs on the left depict Depth and CPP/Depth throughout chest compression in the NHEI group (○) compared with the control group (●). The numbers in brackets denote rats remaining in VF during chest compression as explained in the “Experimental groups and drugs” section. One rat in the cariporide group spontaneously defibrillated coincident with the end of the 8th minute of chest compression and therefore did not require electrical shocks but was included for the aggregate measurement of coronary perfusion pressure and depth of compression. The bar graphs on the right depict the effects of the interventions at the last minute of chest compression before termination of VF spontaneously or by delivery of electrical shocks, which occurred between minute 3 and minute 8 of chest compression. Values are means ± SEM. †p < 0.01, ‡p < 0.001 vs control by Student's t-test; **p < 0.01, ***p < 0.001 vs control by one-way ANOVA using Holm-Sidak's test for multiple comparisons; *p < 0.05 vs control by one-way ANOVA using Dunn's test for multiple comparisons.

Figure 2

Shown are the number and energy level of electrical shocks required to terminate ventricular fibrillation (Resuscitation) and the number and energy level of electrical shocks required in the event that VF recurred after successful defibrillation with return of spontaneous circulation (Post-Resuscitation), in rats that received control solution, AVE4454B (AVE), or cariporide (CRP). The number in brackets denotes number of shocks. Rats marked with “x” failed to regain spontaneous circulation. Symbols ●, ■, and ◆ denote 3, 5, and 7 joules respectively. *p < 0.05 vs control by one-way ANOVA using Dunn's test for multiple comparisons for resuscitation shocks.

Figure 3

Survival curves in rats that received vehicle control solution, AVE4454B (AVE), or cariporide (CRP). The graphs on the left depict survival curves for all rats subjected to ventricular fibrillation and graphs on the right only for rats that had return of spontaneous circulation (ROSC) after defibrillation. The graphs on the top depict survival for the individual interventions and on the bottom survival for the AVE and CRP groups combined (NHEI). The number of rats that survived for post-resuscitation 240-minute interval relative to the corresponding cohort is shown for each curve in parentheses. **p < 0.01 vs control by Gehan-Breslow analysis using Holm-Sidak's test for multiple comparisons; †p = 0.01 vs control by Gehan-Breslow analysis.

Figure 4

Scatterplots depicting the relationship between plasma cytochrome c and mean aortic pressure (MAP), cardiac index (CI), left ventricular stroke work index (LVSWI), and the maximal rate of left ventricular pressure rise (+dP/dtmax) at 240 minutes post-resuscitation in rats treated with AVE4454B (○) or cariporide (●). There was only one survival in the control group at 240 minutes and was removed from the analysis.