Major myocardial abnormalities occur during cardiac arrest and resuscitation including intracellular acidosis-partly caused by CO accumulation-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 CO-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... More
Major myocardial abnormalities occur during cardiac arrest and resuscitation including intracellular acidosis-partly caused by CO accumulation-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 CO-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 Ca 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.
