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

Ayoub, Iyad M.; Kolarova, Julieta D; Kantola, Ronald L.; Radhakrishnan, Jeejabai; Wang, Sufen; Gazmuri, Raúl J.

doi:10.1097/01.ccm.0000280569.87413.74

Cited by 33 publications

(40 citation statements)

References 41 publications

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“…Its effect on myocardial carbon dioxide concentration is not clear. Be that as it may, elegant studies of cardiac arrest induced by ventricular fibrillation revealed improvement in cardiac function during fibrillation [25] and significant attenuation of postresuscitation ventricular arrhythmias including prevention of recurrent episodes of ventricular fibrillation with cariporide and other NHE1 inhibitors in both pig and rat models (table 1) [26,27,28,29,30,31,32]. …”

Section: Cardiac Arrestmentioning

confidence: 99%

Role of NHE1 in the Cellular Dysfunction of Acute Metabolic Acidosis

Wu¹,

Kraut²

2014

Am J Nephrol

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Background: Metabolic acidosis is associated with impaired cellular function. This has been attributed to the accompanying reduction in intracellular and interstitial pH of the myocardium. Recent studies suggest that activation of the cellular Na⁺-H⁺ exchanger NHE1 might contribute to myocardial dysfunction. This review examines the experimental evidence which supports the role of NHE1 in the genesis of acidosis-induced cellular dysfunction, the benefits of its inhibition, and the type of acidosis that might benefit from therapy. Summary: Information was obtained by searching MEDLINE for articles published between 1969 and 2013 using the terms: NHE1, metabolic acidosis, lactic acidosis, ischemia-reperfusion, shock, resuscitation, high anion gap acidosis, and non-gap acidosis. Each article was also reviewed for additional suitable references. Nineteen manuscripts published between 2002 and 2013 assessed the impact of inhibition of NHE1 on cellular function. They revealed that NHE1 is activated with metabolic acidosis associated with hypoxia, hypoperfusion, hemorrhagic shock, and sepsis. This was associated with a rise in cellular sodium and calcium and cardiac dysfunction including reduced contractility and a predisposition to cardiac arrhythmias. Inhibition of NHE1 with specific inhibitors improved cardiac function, reduced blood and tissue levels of proinflammatory cytokines, and decreased mortality. Key Message: These results suggest that use of inhibitors of NHE1 might be worthwhile in the treatment of some types of acute metabolic acidosis, specifically the lactic acidosis associated with hypoxia, hemorrhagic shock, and cardiac arrest. Its potential role in the treatment of other forms of acute metabolic acidosis remains to be determined.

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Section: Cardiac Arrestmentioning

confidence: 99%

Role of NHE1 in the Cellular Dysfunction of Acute Metabolic Acidosis

Wu¹,

Kraut²

2014

Am J Nephrol

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“…45 However, ischemic contracture is associated with profound reductions in myocardial ATP and often leads to a “stony heart” heralding irreversible ischemic injury. 46 Reductions in left ventricular distensibility observed during cardiac resuscitation is a different phenomenon: (1) it occurs much earlier than the “stony heart” starting coincident with reperfusion during the resuscitation effort, 41,42 (2) it is associated with less ATP depletion, 40 (3) it has been attributed to myocardial energy deficit compounded by cytosolic and mitochondrial Ca 2+ overload precluding complete relaxation of individual cardiomyocytes, (4) it evolves into diastolic dysfunction upon return of spontaneous circulation, 47 (5) it is largely reversible, 48 and (6) it is amenable to therapeutic intervention (Figure 4). …”

Section: Myocardial Abnormalities During Cardiac Resuscitationmentioning

confidence: 99%

“…One line relates to work using NHE-1 inhibitors in various animal models of cardiac arrest over a period of approximately 10 years. 40,42,49,65–70 The other line relates to more recent work using erythropoietin in a rat model of cardiac arrest 71 and in a small clinical study in patients suffering out-of-hospital cardiac arrest. 72 Both lines of research support the rationale and feasibility of using either an NHE-1 inhibitor or erythropoietin for preservation of left ventricular myocardial distensibility during cardiac resuscitation.…”

Section: Interventions Targeting Mitochondrial Functionmentioning

confidence: 99%

Protecting Mitochondrial Bioenergetic Function During Resuscitation from Cardiac Arrest

Gazmuri

Radhakrishnan

2012

Critical Care Clinics

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Synopsis Successful resuscitation from cardiac arrest requires reestablishment of aerobic metabolism by reperfusion with oxygenated blood of tissues that have been deprived of oxygen for variables periods of time. However, reperfusion concomitantly activates pathogenic mechanisms known as “reperfusion injury.” At the core of reperfusion injury are mitochondria, playing a critical role as effectors and targets of such injury. Mitochondrial injury compromises oxidative phosphorylation and also prompts release of cytochrome c to the cytosol and bloodstream where it correlates with severity of injury. Main drivers of such injury include Ca2+ overload and oxidative stress. Preclinical work shows that limiting myocardial cytosolic Na+ overload at the time of reperfusion attenuates mitochondrial Ca2+ overload and maintains oxidative phosphorylation yielding functional myocardial benefits that include preservation of left ventricular distensibility. Preservation of left ventricular distensibility enables hemodynamically more effective chest compression. Similar myocardial effect have been reported using erythropoietin hypothesized to protect mitochondrial bioenergetic function presumably through activation of pathways similar to those activated during preconditioning. Incorporation of novel and clinical relevant strategies to protect mitochondrial bioenergetic function are expected to attenuate injury at the time of reperfusion and enhance organ viability ultimately improving resuscitation and survival from cardiac arrest.

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“…Effects of NHE-1 inhibition on resuscitation: Research over the last decade in our laboratory using various translational rat and pig models of cardiac arrest has shown consistent myocardial benefit associated with inhibition of NHE-1 activity during resuscitation from VF. (10,17,23,28,(37)(38)(39)(40)(41)(56)(57)(58)(59)(60) Mechanistically, these benefits are associated with less cytosolic Na+ overload, less mitochondrial Ca2+ overload, and preservation of oxidative phosphorylation. Some of these studies, highlighting key aspects of NHE-1 inhibition during resuscitation, are succinctly discussed below.…”

Section: Therapeutic Interventionsmentioning

confidence: 99%

“…(10,17,23,28,(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55) Research over the last decade in our laboratory using various translational rat and pig models of cardiac arrest has shown consistent myocardial benefit associated with inhibition of NHE-1 activity during resuscitation from VF. (10,17,23,28,(37)(38)(39)(40)(41)(56)(57)(58)(59)(60) Mechanistically, these benefits are associated with less cytosolic Na+ overload, less mitochondrial Ca2+ overload, and preservation of oxidative phosphorylation. The other relates to more recent work using erythropoietin in a rat model of cardiac arrest (42) and in a small clinical study in patients suffering out-of-hospital cardiac arrest.…”

Section: Therapeutic Interventionsmentioning

confidence: 99%

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

Gazmuri

Ayoub

Radhakrishnan

2010

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

Abstract: 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.

Cited by 33 publications

References 41 publications

Role of NHE1 in the Cellular Dysfunction of Acute Metabolic Acidosis

Role of NHE1 in the Cellular Dysfunction of Acute Metabolic Acidosis

Protecting Mitochondrial Bioenergetic Function During Resuscitation from Cardiac Arrest

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

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