Sodium-hydrogen Exchanger Isoform-1 Research Articles

Screening of 5- and 6-Substituted Amiloride Libraries Identifies Dual-uPA/NHE1 Active and Single Target-Selective Inhibitors

The K+-sparing diuretic amiloride shows off-target anti-cancer effects in multiple rodent models. These effects arise from the inhibition of two distinct cancer targets: the trypsin-like serine protease urokinase-type plasminogen activator (uPA), a cell-surface mediator of matrix degradation and tumor cell invasiveness, and the sodium-hydrogen exchanger isoform-1 (NHE1), a central regulator of transmembrane pH that supports carcinogenic progression. In this study, we co-screened our library of 5- and 6-substituted amilorides against these two targets, aiming to identify single-target selective and dual-targeting inhibitors for use as complementary pharmacological probes. Closely related analogs substituted at the 6-position with pyrimidines were identified as dual-targeting (pyrimidine 24 uPA IC50 = 175 nM, NHE1 IC50 = 266 nM, uPA selectivity ratio = 1.5) and uPA-selective (methoxypyrimidine 26 uPA IC50 = 86 nM, NHE1 IC50 = 12,290 nM, uPA selectivity ratio = 143) inhibitors, while high NHE1 potency and selectivity was seen with 5-morpholino (29 NHE1 IC50 = 129 nM, uPA IC50 = 10,949 nM; NHE1 selectivity ratio = 85) and 5-(1,4-oxazepine) (30 NHE1 IC50 = 85 nM, uPA IC50 = 5715 nM; NHE1 selectivity ratio = 67) analogs. Together, these amilorides comprise a new toolkit of chemotype-matched, non-cytotoxic probes for dissecting the pharmacological effects of selective uPA and NHE1 inhibition versus dual-uPA/NHE1 inhibition.

Abstract 257: Ventricular Fibrillation Amplitude Spectral Area to Assess the Myocardial Effect of Hemodynamic and Metabolic Interventions During Cardiac Resuscitation in a Rat Model

Introduction: The amplitude spectral area (AMSA) of ventricular fibrillation (VF) has been shown to track the myocardial energy state and to predict the effect of defibrillation. We measured AMSA in a rat model of VF and assessed the effects of α-methylnorepinephrine (α-MNE) - a selective peripheral α 2 -adrenoreceptor agonist - given to increase the coronary perfusion pressure without myocardial β 1 -adrenoceptor stimulation and the effects of zoniporide (ZNP) - an inhibitor of the sodium-hydrogen exchanger isoform-1 - given to protect mitochondrial bioenergetic function from reperfusion injury. Methods: VF was electrically induced in 48 rats and left untreated for 8 minutes. Chest compression was then started and defibrillation attempted 8 minutes later. Rats were randomized to receive a 3-mg/kg bolus of ZNP or 0.9% NaCl control (Ctr) before starting chest compression and a 100-μg/kg bolus of α-MNE or 0.9% NaCl control (Ctr) at 2 minutes of chest compression yielding four groups of 12 rats each; ZNP/α-MNE, ZNP/Ctr, Ctr/α-MNE, and Ctr/Ctr. Results: AMSA (mV·Hz; mean±SEM) was 34.9±1.5 at minute one after induction of VF and decreased to 2.6±0.2 at minute eight. With chest compression, AMSA gradually increased attaining different levels among groups (p<0.001). At minute seven of chest compression, AMSA was the highest with ZNP/α-MNE (29.9±2.5; p=0.012 vs Ctr/α-MNE and p<0.001 vs Ctr/Ctr) followed by ZNP/Ctr (24.1±2.5; p=0.016 vs Ctr/Ctr), Ctr/α-MNE (18.9±2.3), and Ctr/Ctr (12.9±2.6). Survival at 240 minutes differed among groups (p=0.007) with the highest survival with ZNP/α-MNE. Analysis of the independent effects of the interventions revealed that AMSA at minute seven was significantly higher with ZNP (27.2±2.6 vs 16.2±1.6; p<0.001) but not with α-MNE (22.9±2.1 vs 18.6±2.8; p=1.000). Survival was significantly higher with ZNP (18/24 vs 7/24; p=0.004) but not with α-MNE (12/24 vs 13/24; p=1.000). Conclusions: AMSA was the highest when ZNP was combined with α-MNE; a combination that also resulted in the highest 240-minute survival. This effect was primarily linked to ZNP without excluding a positive interaction with α-MNE. Accordingly, AMSA may also serve to assess the myocardial effects of metabolic interventions during cardiac resuscitation.

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

Out-of-hospital sudden cardiac arrest is a major public health problem with an overall survival of less than 5%. Upon cardiac arrest, cessation of coronary blood flow rapidly leads to intense myocardial ischemia and activation of the sarcolemmal Na+-H+ exchanger isoform-1 (NHE-1). NHE-1 activation drives Na+ into cardiomyocytes in exchange for H+ with its exchange rate intensified upon reperfusion during the resuscitation effort. Na+ accumulates in the cytosol driving Ca2+ entry through the Na+-Ca2+ exchanger, eventually causing cytosolic and mitochondrial Ca2+ overload and worsening myocardial injury by compromising mitochondrial bioenergetic function. We have reported clinically relevant myocardial effects elicited by NHE-1 inhibitors given during resuscitation in animal models of ventricular fibrillation (VF). These effects include: (a) preservation of left ventricular distensibility enabling hemodynamically more effective chest compressions, (b) return of cardiac activity with greater electrical stability reducing post-resuscitation episodes of VF, (c) less post-resuscitation myocardial dysfunction, and (d) attenuation of adverse myocardial effects of epinephrine; all contributing to improved survival in animal models. Mechanistically, NHE-1 inhibition reduces adverse effects stemming from Na+–driven cytosolic and mitochondrial Ca2+ overload. We believe the preclinical work herein discussed provides a persuasive rationale for examining the potential role of NHE-1 inhibitors for cardiac resuscitation in humans.

Abstract 148: Zoniporide Combined with α-Methylnorepinephrine Appears Highly Effective for Resuscitation from Cardiac Arrest in a Rat Model of Ventricular Fibrillation

Background: We have reported in rat and swine models of cardiac arrest that sodium hydrogen exchanger isoform-1 (NHE-1) inhibition facilitates resuscitation, ameliorates myocardial dysfunction, and improves survival. Others have reported that α-methylnorepinephrine (α-MNE) - a selective α2-adrenoreceptor agonist - is superior to epinephrine given its lack of β-agonist effects. We examined in a rat model of VF and closed-chest resuscitation the effects of combining the NHE-1 inhibitor zoniporide (ZNP) with α-MNE. Methods: VF was electrically induced in 32 male retired breeder Sprague-Dawley rats and left untreated for 8 minutes after which resuscitation was attempted by an 8 minute interval of chest compression and delivery of electrical shocks. Rats were randomized 1:1:1:1 to receive a 3 mg/kg bolus of ZNP or 0.9% NaCl before starting chest compression and a 100 μg/kg bolus of α-MNE or its vehicle at minute 2 of chest-compressions establishing 4 groups of 8 rats each. Successfully resuscitated rats were monitored for 240 minutes. Results: The number of rats that had return of spontaneous circulation and then survived 240 min were: α-MNE(-)/ZNP(-) 4 and 2; α-MNE(-)/ZNP(+) 5 and 5; α-MNE(+)/ZNP(-) 2 and 1; and α-MNE(+)/ZNP(+) 7 and 7 yielding a statistically significant effect on overall survival times corresponding to 105 ± 114, 150 ± 124, 58 ± 108, and 210 ± 85 min, respectively (p < 0.045). Post-resuscitation lactate levels were attenuated in all treatment groups with the greatest effect by the α-MNE(+)/ZNP(+) combination without major differences in hemodynamic function (Table). Conclusion: We confirm a beneficial effect resulting from the combination of ZNP (given to attenuate myocardial reperfusion injury) and α-MNE (given to augment peripheral vascular resistance during chest compression without the detrimental actions of epinephrine). The proposed combination may prove to be a highly effective novel strategy for resuscitation from cardiac arrest.

Abstract 186: NHE-1 Inhibition Reduces Rigor and Hypercontracture in Isolated Cardiomyocytes During Ischemia and Reperfusion

Background: During ischemia, anaerobic metabolism prompts intracellular acidosis with activation of the sodium hydrogen exchanger isoform-1 (NHE-1), resulting in intracellular Na+ overload consequent to reductions in Na+-K- ATPase activity. The Na+ excess prompts Ca2+ entry through the sodium-calcium exchanger, leading to Ca+ overload. Ca+ overload, predisposes cells to hypercontracture upon reoxygenation. NHE-1 inhibition reduces Na+ overload and the subsequent Ca+ overload. We developed a programmable system to model ischemia and reperfusion by dynamically blending O2, CO2, and N2 and used it to model changes in gas tension at the tissue levels during ischemia and reperfusion. We validated the model by comparing the effects of reoxygenation with and without the NHE-1 inhibitor zoniporide in isolated adult rat cardiomyocytes. Methods: The set-up included: (i) a programmable dynamic gas blender developed by us, (ii) equilibration of ischemic buffer with anoxic gas mixture at 3-5 LPM and perfusion within an imaging chamber at 2.5 ml/min, (iii) a glass reservoir and stainless steel tubing to avoid gas diffusion, (iv) an acrylic hood, constantly flushed with anoxic gas mixture, covering the chamber on the stage of the microscope, and (v) an O2 microelectrode to continuously monitor PO2 in the chamber. The set-up resulted in PO2 of 0 mmHg during ischemia. The cells were subjected to 15 min of baseline stabilization, 45 min of ischemia, and 120 min of reperfusion. Zoniporide (at a final concentration of 3 μM) was administered starting at 10 min of ischemia and was maintained throughout reperfusion. Results: Zoniporide significantly attenuated development of rigor and subsequent hypercontracture (P=0.001, Gehan Breslow survival analysis). Conclusion: The newly develop system reproduced at the cell level effects of ischemia and reperfusion. These effects were attenuated by NHE-1 inhibition as it has been reported in isolated organs and in the in situ heart.

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.

NHE-1 Inhibitors and Erythropoietin for Maintaining Myocardial Function during Cardiopulmonary Resuscitation

Efforts to successfully restore life in cardiac arrest victims are formidably challenging. They require not only that cardiac activity be initially reestablished but that injury to vital organs be prevented or minimized. In this article, we discuss the effects that cardiac arrest and resuscitation have on the myocardium, describing first the functional myocardial abnormalities that occur during cardiac resuscitation, which may limit the ability to reestablish cardiac activity.&nbsp;We then discuss strategies for minimizing myocardial injury and examine novel therapies aimed at minimizing ischemia and reperfusion injury. Finally, we discuss sodium-hydrogen exchanger isoform-1(NHE-1) inhibitors and erythropoietin for maintaining myocardial function during cardiopulmonary resuscitation.

Protecting mitochondrial bioenergetic function

Reversal of cardiac arrest requires reestablishment of aerobic metabolism by reperfusion with oxygenated blood of tissues that have been ischemic for variables periods of time. However, reperfusion concomitantly activates a myriad of pathogenic mechanisms causing what is known as “reperfusion injury.” At the center of reperfusion injury are mitochondria, playing a critical role as effectors and targets of injury. Mitochondrial injury compromises oxidative phosphorylation and the ability to regenerate Adenosine-5'-triphosphate (ATP); i.e., bioenergetic function. Thus targeting mitochondria to protect bioenergetic function may represent a novel concept in resuscitation with the potential for altering clinical practice. We have identified sodium-hydrogen exchanger isoform-1 (NHE)-1 inhibition and erythropoietin as attractive candidate drugs for this purpose and demonstrated corresponding functional and clinical benefits. Further work on the subject may pave the way for further scientific discover focused on greater understating of underlying cell mechanisms, identification of additional and perhaps more potent strategies, and develop means for effective drug delivery.

Cariporide given during resuscitation promotes return of electrically stable and mechanically competent cardiac activity

Episodes of ventricular fibrillation (VF) and myocardial dysfunction commonly occur after cardiac resuscitation compromising the return of stable circulation. We investigated in a pig model of VF whether limiting Na +-induced cytosolic Ca 2+ overload using the sarcolemmal sodium-hydrogen exchanger isoform-1 (NHE-1) inhibitor cariporide promotes resuscitation with stable circulation. Methods VF was electrically induced in 20 male pigs and left untreated for 6 min after which CPR was initiated and continued for 8 min before attempting defibrillation. Pigs were randomized to receive 3-mg/kg cariporide ( n = 10) or 0.9%-NaCl ( n = 10) before chest compression. Results Seven of 10 pigs in each group were successfully resuscitated and survived 2 h. Cariporide ameliorated post-resuscitation ventricular ectopic activity such that fewer singlets (5 ± 5 vs. 26 ± 21; p < 0.05) and fewer bigemini (1 ± 3 vs. 33 ± 25; p < 0.05) were observed during the initial 5 min post-resuscitation. Additionally, cariporide-treated pigs did not require additional post-resuscitation shocks for ventricular tachycardia or recurrent VF (0.0 ± 0.0 vs. 5.3 ± 7.8 shocks; p = 0.073). During the initial 60 min cariporide-treated pigs had higher, cardiac index (6.1 ± 0.7 vs. 4.4 ± 1.1 L/min/m 2; p < 0.01), left ventricular stroke work index (45 ± 9 vs. 36 ± 10 gm m/beat/m 2; p < 0.05), and numerically higher mean aortic pressure (104 ± 11 vs. 91 ± 12 mmHg; p = 0.054). Conclusion Cariporide administered at the start of chest compression may help restore electrically and mechanically stable circulation after resuscitation from cardiac arrest.

Activation of caspase-3 may not contribute to postresuscitation myocardial dysfunction

We have previously reported that postresuscitation myocardial dysfunction is accompanied by the release of cytochrome c and caspase-3 activation. We now investigated the role of caspase-3 activation by examining whether such process prompts apoptotic DNA fragmentation, whether caspase-3 inhibition attenuates myocardial dysfunction, and whether myocardial protective effects of sodium-hydrogen exchanger isoform-1 (NHE-1) inhibition involve caspase-3 inhibition using a rat model of ventricular fibrillation (VF) of closed-chest resuscitation. Resuscitation after 4 or 8 min of untreated VF caused significant reductions in left ventricular stroke work index averaging 23% of sham control rats at 4 h postresuscitation. Left ventricular dysfunction was accompanied by increases in cytosolic cytochrome c, decreases in pro- and cleaved caspase-9 fragments, increases in 17-kDa caspase-3 fragments, and increases in caspase-3 activity indicating the activation of the mitochondrial apoptotic pathway but without evidence of apoptotic DNA fragmentation. In addition, levels of heat shock protein 70 were increased and levels of X-linked inhibitor of apoptosis protein and alphabeta-crystallin were preserved, all of which can exert antiapoptotic effects. In a separate series, the caspase-3 inhibitor z-Asp-Glu-Val-Asp chloromethyl ketone given before the induction of VF failed to prevent postresuscitation myocardial dysfunction despite reductions in caspase-3 activity (2.3 +/- 0.5 vs. 1.3 +/- 0.5 pmol fluorophore AFC released.mg protein(-1).min-1; P < 0.03). Treatment with the NHE-1 inhibitor cariporide had no effect on caspase-3 activity. Accordingly, in this rat model of VF and severe postresuscitation myocardial dysfunction, activation of caspase-3 did not lead to DNA fragmentation or contribute to myocardial dysfunction. Concomitant activation of intrinsic antiapoptotic mechanisms could play a protective role downstream to caspase-3 activation.

Sodium-Hydrogen Exchange Inhibition by Cariporide to Reduce the Risk of Ischemic Cardiac Events in Patients Undergoing Coronary Artery Bypass Grafting: Results of the EXPEDITION Study

The EXPEDITION study addressed the efficacy and safety of inhibiting the sodium hydrogen exchanger isoform-1 (NHE-1) by cariporide in the prevention of death or myocardial infarction (MI) in patients undergoing coronary artery bypass graft surgery. The premise was that inhibition of NHE-1 limits intracellcular Na accumulation and thereby limits Na/Ca-exchanger-mediated calcium overload to reduce infarct size. High-risk coronary artery bypass graft surgery patients (n = 5,761) were randomly allocated to receive either intravenous cariporide (180 mg in a 1-hour preoperative loading dose, then 40 mg per hour over 24 hours and 20 mg per hour over the subsequent 24 hours) or placebo. The primary composite endpoint of death or MI was assessed at 5 days, and patients were followed for as long as 6 months. At 5 days, the incidence of death or MI was reduced from 20.3% in the placebo group to 16.6% in the treatment group (p = 0.0002). Paradoxically, MI alone declined from 18.9% in the placebo group to 14.4% in the treatment group (p = 0.000005), while mortality alone increased from 1.5% in the placebo group to 2.2% with cariporide (p = 0.02). The increase in mortality was associated with an increase in cerebrovascular events. Unlike the salutary effects that were maintained at 6 months, the difference in mortality at 6 months was not significant. The EXPEDITION study is the first phase III myocardial protection trial in which the primary endpoint was achieved and proof of concept demonstrated. As a result of increased mortality associated with an increase in cerebrovascular events, it is unlikely that cariporide will be used clinically. The findings suggest that sodium hydrogen exchanger isoform-1 inhibition holds promise for a new class of drugs that could significantly reduce myocardial injury associated with ischemia-reperfusion injury.

Zoniporide preserves left ventricular compliance during ventricular fibrillation and minimizes postresuscitation myocardial dysfunction through benefits on energy metabolism*

To investigate whether sodium-hydrogen exchanger isoform-1 (NHE-1) inhibition attenuates myocardial injury during resuscitation from ventricular fibrillation through effects on energy metabolism, using an open-chest pig model in which coronary perfusion was controlled by extracorporeal circulation. Randomized controlled animal study. University research laboratory. Male domestic pigs. Ventricular fibrillation was electrically induced and left untreated for 8 mins, after which extracorporeal circulation was started and its flow adjusted to maintain a coronary perfusion pressure of 10 mm Hg. After 10 mins of extracorporeal circulation, restoration of spontaneous circulation was attempted by epicardial defibrillation and gradual reduction in extracorporeal flow. Two groups of eight pigs each were randomized to receive the NHE-1 inhibitor zoniporide (3 mg.kg-1) or vehicle control immediately before starting extracorporeal circulation. Identical extracorporeal flows (approximately = 9% of baseline cardiac index) were required in zoniporide and control groups to attain the target coronary perfusion pressure, resulting in comparable left anterior descending coronary artery blood flow (9 +/- 1 and 10 +/- 1 mL.min-1) and resistance (0.10 +/- 0.01 and 0.10 +/- 0.01 dyne.sec.cm(-5)). Yet zoniporide prevented reductions in left ventricular volume and wall thickening while favoring higher myocardial creatine phosphate to creatine ratios (0.14 +/- 0.03 vs. 0.06 +/- 0.01, p < .05), lower myocardial adenosine (0.7 +/- 0.1 vs. 1.3 +/- 0.2, p < .05), and lower myocardial lactate (80 +/- 9 vs. 125 +/- 6 mmol.kg-1, p < .001). Postresuscitation, zoniporide-treated pigs had higher left ventricular ejection fraction (0.57 +/- 0.07 vs. 0.29 +/- 0.05, p < .05) and higher cardiac index (4.8 +/- 0.4 vs. 3.4 +/- 0.2 L.min-1.m-2, p < .05). Zoniporide ameliorated myocardial injury during resuscitation from ventricular fibrillation through beneficial effects on energy metabolism without effects on coronary vascular resistance and coronary blood flow.

Beyond ion translocation: structural functions of the sodium–hydrogen exchanger isoform-1

The sodium-hydrogen exchanger isoform-1 (NHE1) functions in intracellular pH and cell volume homeostasis by catalyzing an electroneutral exchange of extracellular sodium and intracellular hydrogen. Recent studies have revealed the structural functions of NHE1 as an anchor for actin filaments and a scaffold for an ensemble of signaling proteins. This review highlights how these functions contribute to NHE1 regulation of biochemical events and cell behaviors. New data confirming nontransport structural functions of NHE1 suggest reexamining how NHE1 regulates cell functions. Cell survival, cell substrate adhesion, and organization of the actin cytoskeleton are confirmed to be regulated through actin anchoring by NHE1 and likely by NHE1-dependent scaffolding of signaling proteins. A role for NHE1 in mechanotransduction is emerging and a challenge of future studies is to determine whether structural functions of NHE1 are important for mechanoresponsiveness. This review highlights evidence for the nontransport functions of NHE1 and describes how the structural functions are integrated with ion translocation to regulate a range of cellular processes. Nontransporting features of NHE1 are analogous to recently observed nonconducting actions of ion channels in regulating cell behaviors and represent an emerging paradigm of ion transporters as multifunctional proteins.

Taste Receptors in the Gastrointestinal Tract III. Salty and sour taste: sensing of sodium and protons by the tongue

Taste plays an essential role in food selection and consequently overall nutrition. Because salt taste is appetitive, humans ingest more salt than they need. Acids are the source of intrinsically aversive sour taste, but in mixtures with sweeteners they are consumed in large quantities. Recent results have provided fresh insights into transduction and sensory adaptation for the salty and sour taste modalities. The sodium-specific salt taste receptor is the epithelial sodium channel whereas a nonspecific salt taste receptor is a taste variant of the vanilloid receptor-1 nonselective cation channel, TRPV1. The proximate stimulus for sour taste is a decrease in the intracellular pH of a subset of acid-sensing taste cells, which serves as the input to separate transduction pathways for the phasic and tonic parts of the sour neural response. Adaptation to sour arises from the activation of the basolateral sodium-hydrogen exchanger isoform-1 by an increase in intracellular calcium that sustains the tonic phase of the sour taste response.

The Case for Sodium-Hydrogen Exchanger Isoform-1 Inhibition During Cardiac Resuscitation Remains Strong

The Case for Sodium-Hydrogen Exchanger Isoform-1 Inhibition During Cardiac Resuscitation Remains Strong

The Case for Sodium-Hydrogen Exchanger Isoform-1 Inhibition During Cardiac Resuscitation Remains Strong

The Case for Sodium-Hydrogen Exchanger Isoform-1 Inhibition During Cardiac Resuscitation Remains Strong

Cariporide minimizes adverse myocardial effects of epinephrine during resuscitation from ventricular fibrillation*

Epinephrine given during closed-chest resuscitation increases blood flow across the coronary and cerebral circuits. However, epinephrine worsens reperfusion arrhythmias and intensifies postresuscitation myocardial dysfunction. We investigated whether cariporide-a selective sodium-hydrogen exchanger isoform-1 inhibitor-could ameliorate such adverse effects without diminishing its vasopressor actions. Randomized animal study. University-based animal laboratory. Twenty-four anesthetized male domestic pigs (29-43 kg). Ventricular fibrillation was electrically induced and left untreated for 8 mins. Pigs were randomized to receive after 2 mins of chest compression a 3 mg/kg bolus of cariporide (n = 8), a 0.02 mg/kg bolus of epinephrine (n = 8), or a combination of cariporide and epinephrine (n = 8). Additional doses of epinephrine were given if the coronary perfusion pressure decreased below 15 mm Hg. Successfully resuscitated pigs were observed for 72 hrs. The averaged coronary perfusion pressure was higher in the epinephrine (34 +/- 11 mm Hg, p = .001) and cariporide/epinephrine (35 +/- 10 mm Hg, p < .001) groups compared with the cariporide group (15 +/- 6 mm Hg). All pigs in the epinephrine and cariporide/epinephrine groups but only six in the cariporide group were successfully resuscitated and survived 72 hrs. During the immediate postresuscitation period, four of eight pigs in the epinephrine group had episodes of recurrent ventricular fibrillation or pulseless ventricular tachycardia requiring additional electrical shocks (7.0 +/- 6.4) but none in the cariporide and cariporide/epinephrine groups (chi-square, p = .008). Myocardial dysfunction occurred early after return of spontaneous circulation but only in the epinephrine group. The combined administration of cariporide and epinephrine prompted adequate pressor effects during chest compression and facilitated reestablishment of cardiac activity without episodes of recurrent ventricular fibrillation or transient myocardial dysfunction as with epinephrine alone.

Cariporide Potentiates the Effects of Epinephrine and Vasopressin by Nonvascular Mechanisms During Closed-Chest Resuscitation

Background : The efficacy of vasopressor therapy during closed-chest resuscitation is limited and decreases over time. We previously reported that sodium-hydrogen exchanger isoform-1 inhibition during ventricular fibrillation (VF) using cariporide ameliorates ischemic contracture and enhances the efficacy of chest compression. We currently investigated whether cariporide could potentiate pressor responses to epinephrine and vasopressin Methods : VF was induced and left untreated for 12 min in two series of 16 rats each. Chest compression was then started and the depth adjusted within the initial 2 min to attain an aortic diastolic pressure between 26 and 28 mm Hg. In one series, rats received boluses of epinephrine (150 μg/kg); in the other series, rats received boluses of vasopressin (0.8 U/kg) to maintain the aortic diastolic pressure > 25 mm Hg. Within each series, rats were randomized to receive a 3 mg/kg bolus of cariporide or 0.9% NaCl immediately before starting chest compression. Defibrillation was attempted at 20 min of VF (8 min of chest compression) Results : Cariporide prompted higher and more sustained coronary perfusion pressures in both the epinephrine group (37 ± 5 mm Hg vs 29 ± 7 mm Hg, p in situ perfusion of the aorta excluded a vascular-mediated effect of cariporide Conclusion : Cariporide enhanced the hemodynamic efficacy of vasopressor agents and improved resuscitation outcomes probably as a result of enhanced forward blood flow without effect on the peripheral vasculature

Cariporide Potentiates the Effects of Epinephrine and Vasopressin by Nonvascular Mechanisms During Closed-Chest Resuscitation&lt;xref rid="AFF1"&gt;&lt;sup&gt;*&lt;/sup&gt;&lt;/xref&gt;

The efficacy of vasopressor therapy during closed-chest resuscitation is limited and decreases over time. We previously reported that sodium-hydrogen exchanger isoform-1 inhibition during ventricular fibrillation (VF) using cariporide ameliorates ischemic contracture and enhances the efficacy of chest compression. We currently investigated whether cariporide could potentiate pressor responses to epinephrine and vasopressin. VF was induced and left untreated for 12 min in two series of 16 rats each. Chest compression was then started and the depth adjusted within the initial 2 min to attain an aortic diastolic pressure between 26 and 28 mm Hg. In one series, rats received boluses of epinephrine (150 microg/kg); in the other series, rats received boluses of vasopressin (0.8 U/kg) to maintain the aortic diastolic pressure > 25 mm Hg. Within each series, rats were randomized to receive a 3 mg/kg bolus of cariporide or 0.9% NaCl immediately before starting chest compression. Defibrillation was attempted at 20 min of VF (8 min of chest compression). Cariporide prompted higher and more sustained coronary perfusion pressures in both the epinephrine group (37 +/- 5 mm Hg vs 29 +/- 7 mm Hg, p < 0.05) and the vasopressin group (36 +/- 5 mm Hg vs 28 +/- 6 mm Hg +/- SD, p < 0.02) even though fewer additional vasopressor doses were required. After resuscitation, cariporide-treated rats had less ventricular ectopic activity, better hemodynamic function, and improved survival scores. In separate experiments, in situ perfusion of the aorta excluded a vascular-mediated effect of cariporide. Cariporide enhanced the hemodynamic efficacy of vasopressor agents and improved resuscitation outcomes probably as a result of enhanced forward blood flow without effect on the peripheral vasculature.

Aminoimidazoles as bioisosteres of acylguanidines: novel, potent, selective and orally bioavailable inhibitors of the sodium hydrogen exchanger isoform-1

Inhibition of the sodium hydrogen exchanger isoform-1 (NHE-1) has been shown to limit damage to the myocardium under ischemic conditions in animals. While most known NHE-1 inhibitors are acylguanidines, this report describes the design and synthesis of a series of heterocyclic inhibitors of NHE-1 including aminoimidazoles with undiminished in vitro activity and oral bioavailability.