Sodium-Hydrogen Exchanger Isoform-1 Inhibition: A Promising Pharmacological Intervention for Resuscitation from Cardiac Arrest

Figures

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  Figure 1. Putative topologic model of an 815-amino acid Na+-H+ exchanger isoform-1. Depicted are 12 transmembrane-spanning segments and a 315-amino acid cytoplasmic hydrophilic carboxyl terminus domain (COOH). The transmembrane domain includes the intracellular H+-sensor site, the functional ion exchange site, and the site where inhibitors bind. The cytoplasmic domain includes sites for regulation via phosphorylation-dependent (P) and phosphorylation-independent mechanisms. Depicted are CaM-A and CaM-B representing high- and low-affinity binding sites for the Ca2+ binding protein calmodulin and CHP, denoting calcineurin homologous protein. Not shown are additional regulatory sites in the cytoplasmic domain for the extracellular signal regulated kinase (ERK1/2), p38 mitogen-activated protein kinase (MAPK), ribosomal S6 kinase (RSK), RhoA kinase, and the tyrosine kinase 2 (Pyk2).

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  Figure 2. Rendition of a cardiomyocyte during ischemia and reperfusion depicting Na+-induced cytosolic and mitochondrial Ca2+ overload consequent to ischemia generating intracellular acidosis while the Na+-K+ pump is inhibited. Ch, channel; NBC, Na+-HCO3− co-transporter; NCX, Na+-Ca2+ exchanger; NHE-1, sodium– hydrogen exchanger isoform-1.

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  Figure 3. (A) Left ventricular wall thickening during chest compression (CC) in an NaCl-treated pig (upper frames) but not in a cariporide-treated pig (lower frames), measured by transesophageal echocardiography at the end of diastole at baseline and between chest compressions (CC) at 2 and 8 min of CPR. (B) Progressive decreases in the coronary perfusion pressure (CPP) coincident with progressive left ventricular (LV) wall thickening in NaCl-treated pigs but not in cariporide-treated pigs. NaCl or cariporide (drug, 3 mg/kg) was given immediately before starting chest compression. Mean ± SEM. * p < 0.05, † p < 0.001 vs. cariporide by one-way ANOVA (Reproduced with permission from Ayoub et al. [14]).

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  Figure 4. Leftward shift of the flow-depth relationship during chest compression elicited by cariporide in rats during VF. Rats were randomized to receive a bolus of cariporide or NaCl before starting chest compression. The first symbol represents data from series 1 and the second symbol from series 2. For paired organs, triangles denote right and squares left. Values are mean ± SEM; * p < 0.05 vs. NaCl by one-way ANOVA in series 2; † p < 0.01 vs. series 1 within each treatment group by one-way ANOVA (Adapted with permission from Kolarova et al. [5]).

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  Figure 5. (A) Coronary perfusion pressure during chest compression in rats that received epinephrine (upper panel) or vasopressin (lower panel). Within each series, 16 rats were randomized to receive immediately before starting chest compression a 3 mg/kg bolus of cariporide or 0.9 % NaCl. With cariporide several rats experienced spontaneous defibrillation. The numbers in brackets indicate rat that remained in ventricular fibrillation. * p < 0.05 vs. NaCl by one-way ANOVA. (B) Combined data from both the epinephrine and vasopressin series in rats randomized to cariporide (n = 16) or NaCl (n = 16). CPPmean = Coronary perfusion pressure averaged through min 3 and 8 of chest compression. * p < 0.05 vs. NaCl by Fisher’s exact test; † p < 0.005, ‡ p < 0.0005 vs. NaCl by one-way ANOVA. (C) Aortic pressure during in situ perfusion. The vasopressor dose was given as a bolus at two minutes of low-flow perfusion. Either cariporide or 0.9% NaCl was infused throughout the low-flow perfusion state in both epinephrine (n = 8) and vasopressin (n = 8) series (adapted with permission from Kolarova et al. [17]).

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  Figure 6. Baseline (BL) and post-resuscitation (PR) left ventricular and hemodynamic function. Numbers in brackets indicate sample size. Values are mean ± SEM. (A) Closed-chest swine model of VF and conventional cardiopulmonary resuscitation in which 20 pigs were randomized to receive cariporide or NaCl control during resuscitation from VF. * p < 0.05; † p < 0.001 vs. control by one-way ANOVA (adapted with permission from Ayoub et al. [21]). (B) Open-chest swine model of VF and resuscitation by extracorporeal circulation in which 16 pigs were randomized to receive zoniporide or NaCl control during resuscitation from VF. * p < 0.05, † p < 0.01 vs. NaCl. In both series administration of the NHE-1 inhibitor during cardiopulmonary resuscitation had a marked beneficial effect on post-resuscitation myocardial function (adapted with permission from Ayoub et al. [6]).

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  Figure 7. Survival curves in rats that received cariporide, AVE4454B, or control solution at the start of chest compression during resuscitation from VF. Shown are survival curves for all rats and survival curves only for rats that had return of spontaneous circulation (ROSC) after defibrillation (Shocks). Top graphs depict survival for the individual interventions. Bottom graphs depict survival for the cariporide and AVE4454B groups combined (NHE-1 Inhibition). ∗ 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 (adapted with permission from Radhakrishnan et al. [22]).

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  Figure 8. Left ventricular intracellular Na+ ([Na+]i), mitochondrial Ca2+ ([Ca2+]m), and cTnI (C) at baseline (BL), at 15 min of untreated VF, at 15 min of VF with chest compression during the last 5 min (VF/CC), and at 60 min post-resuscitation (PR). Black bars denote control rats and white bars denote rats treated with Na+-limiting interventions. Also shown are the effects of individual Na+-limiting interventions. A, AVE4454B and lidocaine vehicle; L, lidocaine and AVE4454B vehicle; and A/L, AVE4454 and lidocaine. Mean ± SEM. ∗ p < 0.05 vs. BL by Kruskal-Wallis one-way ANOVA on ranks using Dunn’s Method for multiple comparisons; † p < 0.05 vs. control by Student’s t-test in PR groups; #two-way ANOVA using time factor (VF/CC vs. PR) and treatment factor (control vs. Na+-limiting interventions) was significant for treatment factor (p = 0.013) for [Na+]i and for both, time factor (p = 0.045) and treatment factor (p = 0.021) for ([Ca2+]m. Also shown is an attenuation of post-resuscitation cTnI increased with the Na+-limiting interventions (∗ p < 0.05 vs. control by Student’s t-test) and an inverse relationship between cardiac work index (CWI) and cTnI levels (r = 0.58, n = 24, p < 0.01)…

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  Figure 9. Myocardial measurements in pigs randomly assigned to receive 3 mg/kg of zoniporide or 0.9% NaCl control after 8 min of untreated ventricular fibrillation (VF) before starting extracorporeal circulation (ECC). Measurements were obtained at baseline (BL), during VF at ECC 4 and 8 min, and post-resuscitation (PR). Each group had eight pigs at baseline. Numbers in brackets indicate when sample size decreased from the initial eight or preceding ones. Shown are the ratio between myocardial phosphocreatine and creatine (pCr/Cr), myocardial lactate content, and (in the inset) the relationship between lactate and pCr/Cr ratio at ECC 8 min. The regression line represents an exponential decay function (R2 = 0.63, p < 0.001). Mean ± SEM; * p < 0.05, ‡ p < 0.001 vs. control by Student’s t-test (adapted with permission from Ayoub et al. [6]).