ABSTRACT
INTRODUCTION: Ischemic postconditioning (IpostC) has been described in both heart and brain. The first aim of this study was to evaluate the effects of IpostC on brain infarct size and neurological function in the middle cerebral artery occlusion (MCAO) model. The second aim was to determine the involvement of the mitochondrial potassium ATP-dependent channel (mitoK(ATP)) opening and its capacity to improve mitochondrial dysfunction induced by ischemia-reperfusion. METHODS: Wistar rats were subjected to 60min MCAO followed by 24-h reperfusion. Postconditioning was performed by 3 cycles of 30-s occlusion-reperfusion at the onset of reperfusion. Three behavioral tests were performed following 24h of reperfusion. Involvement of mitoK(ATP) was determined by the modulation of IpostC effects by 5-hydroxydecanoate (5-HD) and diazoxide. Mitochondrial function after 24h of reperfusion on isolated mitochondria was assessed through mitochondrial oxygen consumption, mitochondrial membrane potential and calcium retention capacity to evaluate impact of IpostC on mitochondrial permeability transition pore (MPTP) opening. RESULTS: IpostC resulted in a 40% decrease in infarct size and improved neurological outcome. These effects were lost when IpostC was delayed by 5min. The administration of diazoxide resulted in a 60% in infarct size. The beneficial effects of IpostC and diazoxide were blocked by 5-HD. Furthermore, 5-HD also blocked the inhibition of MPTP opening by IpostC and diazoxide. The hyperpolarization induced by ischemia-reperfusion was corrected by IpostC without any effect on oxidative phosphorylation. CONCLUSION: Our results confirm ischemic postconditioning-induced neuroprotection. They also support the involvement of mitoK(ATP) opening and its role in inhibiting the opening of MTPT induced by postconditioning.
Subject(s)
Brain Ischemia/physiopathology , Ischemic Postconditioning , KATP Channels/physiology , Mitochondria/physiology , Animals , Behavior, Animal/physiology , Calcium/metabolism , Decanoic Acids/pharmacology , Hydroxy Acids/pharmacology , Infarction, Middle Cerebral Artery/pathology , KATP Channels/antagonists & inhibitors , Male , Membrane Potentials/physiology , Middle Cerebral Artery/physiology , Motor Skills , Nervous System Diseases/etiology , Nervous System Diseases/pathology , Nervous System Diseases/prevention & control , Oxygen Consumption/physiology , Potassium Channel Blockers/pharmacology , Rats , Rats, Wistar , Reperfusion Injury/pathology , Reperfusion Injury/prevention & controlABSTRACT
Reactive oxygen species (ROS) and the mitochondrial ATP-dependent potassium channel (mitoK(+)(-)(ATP)) play a major role in myocardial preconditioning. The same pathways seem to be involved in cerebral preconditioning. The aim of this study was to evaluate ROS involvement during the initial phase of delayed preconditioning and its relationship with mitoK(+)(-ATP) opening in a rat model of cerebral ischemia-reperfusion. Ischemia was induced by a 1-h occlusion of middle cerebral artery followed by a 24-h reperfusion period. A delayed preconditioning was induced by a 3-min ischemia (IPC), an in situ infusion of hydrogen peroxide (H(2)O(2)), or an administration of mitoK(+)(-ATP) agonist diazoxide, 72 h before the ischemia-reperfusion (I/R). IPC was performed in the presence or not of N-acetyl-cysteine (NAC) or 5-hydroxydecanoate (5-HD). A neuroprotection was induced by IPC and administration of H(2)O(2) or diazoxide. The decrease in infarct size was respectively 24.5%, 45.7% and 24.6%. IPC was abolished by 5-HD and NAC, indicating that mitoK(+)(-ATP) and ROS are involved. The protection induced by H(2)O(2) was blocked by 5-HD and diazoxide triggering was abolished by NAC. This strong relationship between ROS and mitoK(+)(-ATP) needs to be clarified as ROS might be involved both upstream and downstream of mitoK(+)(-ATP) opening.
Subject(s)
Hydrogen Peroxide/administration & dosage , Hypoxia-Ischemia, Brain/drug therapy , Oxidants/administration & dosage , Potassium Channels/metabolism , Reactive Oxygen Species/metabolism , Reperfusion Injury/prevention & control , Animals , Hypoxia-Ischemia, Brain/complications , Hypoxia-Ischemia, Brain/pathology , Injections, Intraventricular , Ischemic Preconditioning/methods , Male , Potassium Channels/drug effects , Rats , Rats, Wistar , Reperfusion Injury/etiologyABSTRACT
In clinical practice, the decision to transfuse is linked to the hope of increasing oxygen transport (TO2) to tissues. Physiologic transfusion triggers should progressively replace arbitrary hemoglobin-based transfusion triggers. These 'physiologic' transfusion triggers can be based on signs and symptoms of impaired global oxygenation (lactate, venous O2 saturation [SvO2]) or, even better, of regional tissue oxygenation (electrocardiographic ST-segment, electroencephalographic P300 latency). The SvO2 or its surrogate, the central venous 02 saturation (ScvO2), is a clinical tool which integrates the relationship between whole-body O2 uptake and TO2, and as such can be proposed as a simple physiologic transfusion trigger.
