title: Adverse postresuscitation myocardial effects elicited by buffer-induced alkalemia ameliorated by NHE-1 inhibition in a rat model of ventricular fibrillation.
abstract: Major myocardial abnormalities occur during cardiac arrest and resuscitation including intracellular acidosis-partly caused by CO2accumulation-and activation of the Na+-H+exchanger isoform-1 (NHE-1). We hypothesized that a favorable interaction may result from NHE-1 inhibition during cardiac resuscitation followed by administration of a CO2-consuming buffer upon return of spontaneous circulation (ROSC). Ventricular fibrillation was electrically induced in 24 male rats and left untreated for 8 min followed by defibrillation after 8 min of cardiopulmonary resuscitation (CPR). Rats were randomized 1:1:1 to the NHE-1 inhibitor zoniporide or vehicle during CPR and disodium carbonate/sodium bicarbonate buffer or normal saline (30 ml/kg) after ROSC. Survival at 240 min declined from 100% with Zoniporide/Saline to 50% with Zoniporide/Buffer and 25% with Vehicle/Buffer (P = 0.004), explained by worsening postresuscitation myocardial dysfunction. Marked alkalemia occurred after buffer administration along with lactatemia that was maximal after Vehicle/Buffer, attenuated by Zoniporide/Buffer, and minimal with Zoniporide/Saline [13.3 ± 4.8 (SD), 9.2 ± 4.6, and 2.7 ± 1.0 mmol/l; P ≤ 0.001]. We attributed the intense postresuscitation lactatemia to enhanced glycolysis consequent to severe buffer-induced alkalemia transmitted intracellularly by an active NHE-1. We attributed the worsened postresuscitation myocardial dysfunction also to severe alkalemia intensifying Na+entry via NHE-1 with consequent Ca2+overload injuring mitochondria, evidenced by increased plasma cytochrome c Both buffer-induced effects were ameliorated by zoniporide. Accordingly, buffer-induced alkalemia after ROSC worsened myocardial function and survival, likely through enhancing NHE-1 activity. Zoniporide attenuated these effects and uncovered a complex postresuscitation acid-base physiology whereby blood pH drives NHE-1 activity and compromises mitochondrial function and integrity along with myocardial function and survival.
authors.affiliation: Resuscitation Institute at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois.
authors.forename: Lorissa
authors.initials: L
authors.lastname: Lamoureux
authors.affiliation: Resuscitation Institute at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois.
authors.forename: Jeejabai
authors.initials: J
authors.lastname: Radhakrishnan
authors.affiliation: Department of Chemistry, University of California, Los Angeles, Los Angeles, California.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Mason
authors.affiliation: Medical and Research Services, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California.|Membrane Biology Laboratory, University of California, Los Angeles, Los Angeles, California; and.|Division of Nephrology, Veterans Affairs Greater Los Angeles Healthcare System and David Geffen School of Medicine, Los Angeles, California.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kraut
authors.affiliation: Resuscitation Institute at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois; raul.gazmuri@rosalindfranklin.edu.|Section of Critical Care Medicine, Captain James A. Lovell Federal Health Care Center, North Chicago, Illinois.
authors.forename: Raúl J
authors.initials: RJ
authors.lastname: Gazmuri
mesh_terms: D000818:Animals; D002021:Buffers; D002118:Calcium / Q000378:metabolism; D016887:Cardiopulmonary Resuscitation / Q000379:methods; D004195:Disease Models, Animal; D006146:Guanidines / Q000494:pharmacology; D006323:Heart Arrest / Q000378:metabolism / Q000473:pathology; D006863:Hydrogen-Ion Concentration; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D017693:Sodium Bicarbonate / Q000378:metabolism; D000074082:Sodium-Hydrogen Exchanger 1 / Q000037:antagonists & inhibitors*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D014693:Ventricular Fibrillation / Q000378:metabolism* / Q000473:pathology*
chemical_list: D002021:Buffers; D006146:Guanidines; D011720:Pyrazoles; C452850:Slc9a1 protein, rat; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; C424422:zoniporide; D017693:Sodium Bicarbonate; D012964:Sodium; D002118:Calcium
keywords: CO2-consuming buffer; buffer agents; cardiopulmonary resuscitation; cytochrome c; sodium-hydrogen exchanger isoform-1; ventricular fibrillation