Major myocardial abnormalities occur during cardiac resuscitation including intracellular acidosis - partly caused by CO2 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 CO2-consuming buffer upon return of spontaneous circulation (ROSC). Ventricular fibrillation was electrically induced in 24 male rats and left untreated for 8 minutes followed by defibrillation after 8 minutes of 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 minutes declined from 100% with Zoniporide/Saline to 50% with Zoniporide/Buffer and 25% with Vehicle/Buffer (p=0.004), explained by worsening post-resuscitation 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 (14.0±5.1, 7.3±4.2, and 1.7±0.5 mmol/l; p≤0.002). We attributed the intense post-resuscitation lactatemia to enhanced glycolysis consequent to severe buffer-induced alkalemia transmitted intracellularly by an active NHE-1. We attributed the worsened post-resuscitation 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 post-resuscitation acid-base physiology whereby blood pH drives NHE-1 activity and compromises mitochondrial function and integrity along with myocardial function and survival.
- Buffer agents
- CO2 consuming buffer
- Cardiopulmonary resuscitation
- Sodium-hydrogen exchanger isoform-1
- Cytochrome c
- Copyright © 2016, Journal of Applied Physiology