The Role of Pyruvate-Induced Enhancement of Oxygen Metabolism in Extracellular Purinergic Signaling in The Post- Cardiac Arrest Rat Model

Abstract

Abstract Purine nucleotide adenosine triphosphate (ATP) is a source of intracellular energy maintained by mitochondrial oxidative phosphorylation. However, when released from ischemic cells into the extracellular space, they act as death-signaling molecules (eATP). Despite there being potential benefit in using pyruvate to enhance mitochondria by inducing a highly oxidative metabolic state, its association with eATP levels is still poorly understood. Therefore, while we hypothesized that pyruvate could beneficially increase intracellular ATP with the enhancement of mitochondrial function after cardiac arrest (CA), our main focus was whether a proportion of the raised intracellular ATP would detrimentally leak out into the extracellular space. Indicated by the increased levels in systemic oxygen consumption and brain ATP levels, intravenous administrations of bolus (500 mg/kg) and continuous infusion (1000 mg/kg/hr) of pyruvate successfully increased oxygen and energy metabolism in post 10-min CA rats. The plasma ATP levels increased significantly from 67 ± 11 nM before CA to 227 ± 100 nM 2 hours after the resuscitation, while the pyruvate injection did not affect post-CA ATP levels. Notably, the pyruvate injection improved post-CA cardiac contraction and acidemia (low pH). We also found that pyruvate increased systemic CO2 production post-CA. These data support that pyruvate has therapeutic potential for improving CA outcomes by enhancing oxygen and energy metabolism in the brain and heart, and attenuating intracellular hydrogen iron disorders, but does not exacerbate the death-signaling of eATP in the blood.