The Responses of Tissues from the Brain, Heart, Kidney, and Liver to Resuscitation following Prolonged Cardiac Arrest by Examining Mitochondrial Respiration in Rats

Abstract

Cardiac arrest induces whole-body ischemia, which causes damage to multiple organs. Understanding how each organ responds to ischemia/reperfusion is important to develop better resuscitation strategies. Because direct measurement of organ function is not practicable in most animal models, we attempt to use mitochondrial respiration to test efficacy of resuscitation on the brain, heart, kidney, and liver following prolonged cardiac arrest. Male Sprague-Dawley rats are subjected to asphyxia-induced cardiac arrest for 30 min or 45 min, or 30 min cardiac arrest followed by 60 min cardiopulmonary bypass resuscitation. Mitochondria are isolated from brain, heart, kidney, and liver tissues and examined for respiration activity. Following cardiac arrest, a time-dependent decrease in state-3 respiration is observed in mitochondria from all four tissues. Following 60 min resuscitation, the respiration activity of brain mitochondria varies greatly in different animals. The activity after resuscitation remains the same in heart mitochondria and significantly increases in kidney and liver mitochondria. The result shows that inhibition of state-3 respiration is a good marker to evaluate the efficacy of resuscitation for each organ. The resulting state-3 respiration of brain and heart mitochondria following resuscitation reenforces the need for developing better strategies to resuscitate these critical organs following prolonged cardiac arrest.

The role of decreased cardiolipin and impaired electron transport chain in brain damage due to cardiac arrest

“…Using the CA+CPB model, we previously found that rats did not show any measurable brain function after 30 min of CA and 60 min of CPB, but maintained adequate heart and kidney function (Kim et al, 2014). Consistent with the physiological outcomes, the decrease in mitochondrial state-3 respiration was significantly greater in the brain than other tissues in these resuscitated animals (Kim et al, 2016). This correlation between physiological outcome and mitochondrial respiration activity prompted our current exploration of the mitochondrial ETC for molecular mechanisms of ischemia/reperfusion injury in the brain.…”

Dissociated Oxygen Consumption and Carbon Dioxide Production in the Post–Cardiac Arrest Rat: A Novel Metabolic Phenotype

“…Alterations in mitochondrial function have been detected in a variety of CA models in a variety of animal species 22, 24, 48. Postischemic conditioning has been shown to improve survival in swine resuscitated from CA 49.…”

“…Because of the central role of VO 2 and CO 2 production (VCO 2 ) in mitochondrial energy metabolism, and the evidence that mitochondrial function is altered after resuscitation from CA,22, 23, 24 we hypothesize that the metabolic injury sustained by resuscitated animals will manifest as alterations in systemic VO 2 and VCO 2 . While ex vivo results suggest that VO 2 will decrease, we have purposefully left our hypothesis open because the conditions used in ex vivo experimentation do not reflect the postresuscitation cellular milieu.…”

Initial Blood Ammonia Level Is a Useful Prognostication Tool in Out-of-Hospital Cardiac Arrest ― Multicenter Prospective Study (SOS-KANTO 2012 Study) ―

“…34 Dysfunction of the metabolism in glycolysis (the Krebs cycle) and the ornithine cycle involve the same issue: mitochondria dysfunction in cardiac arrest, which is well studied in animal models. 35,36 An animal model paradigm, however, regardless of how well it is studied, is not the same as the in vivo metabolism of these molecules in humans. Lactate does have a large network that shuttles and metabolizes it everywhere.…”