Myocardial protection during ventricular fibrillation by reduction of proton-driven sarcolemmal sodium influx

Sodium-Hydrogen Exchange Inhibition During Ventricular Fibrillation

“…17,18 Yet, the application of these concepts to the cardiac arrest setting is novel. 1,2 The intense intracellular acidosis that develops during VF after cessation of coronary blood flow is believed to activate the sarcolemmal NHE-1, leading to a protondriven sarcolemmal Na ϩ influx with progressive cytosolic Na ϩ accumulation as the Na ϩ -K ϩ pump fails to extrude Na ϩ during ischemia. 19 Cytosolic Na ϩ overload becomes a "substrate" for ischemia and reperfusion injury.…”

“…We have identified activation of the sarcolemmal sodiumhydrogen exchanger isoform-1 (NHE-1) as a potentially important pathogenic target 1 and demonstrated, in rat models of VF and resuscitation, that NHE-1 inhibition can ameliorate myocardial abnormalities relevant to cardiac resuscitation. 2 In these models, NHE-1 inhibition reduced ischemic contracture during VF (improving the hemodynamic efficacy of chest compression), minimized postresuscitation ventricular ectopic activity (preventing recurrent VF), and lessened postresuscitation myocardial dysfunction.…”

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

“…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.…”

“…(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.…”

G Protein-Coupled Receptors-Induced Activation of Extracellular Signal-Regulated Protein Kinase (ERK) and Sodium-Proton Exchanger Type 1 (NHE1)

“…Further, it has been shown that genetic or pharmacological loss of NHE1 function causes renal tubule epithelial cell apoptosis and renal dysfunction in several models of kidney disease (ureteral obstruction, adriamycin-induced podocyte toxicity, and streptozotocin-induced diabetes), suggesting that NHE1 activity may be beneficial for chronic kidney disease (Schelling & Abu, 2008). Moreover both, ERK and NHE1, have been G Protein-Coupled Receptors-Induced Activation of Extracellular Signal-Regulated Protein Kinase (ERK) and Sodium-Proton Exchanger Type 1 (NHE1) 237 proposed as key therapeutic targets for vascular illnesses, such as congestive heart failure ( Kusumoto et al, 2001), myocardial infraction and reperfusion injury (Avkiran & Marber, 2002), ventricular fibrillation (Gazmuri et al, 2001), and ventricular hypertrophy (Chen et al, 2001). Therefore, studies devoted to the regulatory relationships between NHE1 and ERK have a potential clinical relevance.…”