Inhibition of mitochondrial permeability transition to prevent the post-cardiac arrest syndrome: a pre-clinical study.
OBJECTIVE
Resuscitated cardiac arrest (CA), leading to harmful cardiovascular dysfunction and multiple organ failure, includes a whole-body hypoxia-reoxygenation phenomenon. Opening of the mitochondrial permeability transition pore (mPTP) appears to be a pivotal event in ischaemia-reperfusion injury. We hypothesized that pharmacological inhibition of mPTP opening may prevent the post-CA syndrome.


RESULTS
Anaesthetized New Zealand White rabbits underwent a 15 min primary asphyxial CA and 120 min of reperfusion following resuscitation. At reflow, animals received an intravenous bolus of either cyclosporine A (CsA, 5 mg/kg) or NIM 811 (2.5 mg/kg), two potent inhibitors of mPTP opening, or the CsA vehicle (control). Short-term survival, haemodynamics, regional (sonomicrometry), and global cardiac function (dP/dt and aortic flow) were assessed. We measured markers of cellular injuries and/or organ failure, including troponin Ic release, lacticodehydrogenase, lactate, creatinine, and alanine aminotransferase. Cyclosporine A and NIM 811 significantly improved short-term survival, post-resuscitation cardiac function, as well as liver and kidney failure (P < 0.05). CsA and NIM 811 both attenuated in vitro mPTP opening (calcium retention capacity by spectrofluorimetry) and restored oxidative phosphorylation when compared with controls (P < 0.05).


CONCLUSIONS
These data suggest that pharmacological inhibition of mPTP opening, added to basic life support, attenuates the post-CA syndrome and improves short-term outcomes in the rabbit model.
Cour
Martin
M
INSERM U886-Cardioprotection, Lyon, France.
Loufouat
Joseph
J
Paillard
Mélanie
M
Augeul
Lionel
L
Goudable
Joëlle
J
Ovize
Michel
M
Argaud
Laurent
L
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D016887:Cardiopulmonary Resuscitation; D002316:Cardiotonic Agents / Q000494:pharmacology*; D019069:Cell Respiration / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology*; D006323:Heart Arrest / Q000503:physiopathology / Q000517:prevention & control*; D006439:Hemodynamics / Q000502:physiology; D057775:Ischemic Postconditioning / Q000379:methods; D008297:Male; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects*; D000083162:Mitochondrial Permeability Transition Pore; D009200:Myocardial Contraction; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control; D011817:Rabbits; D019210:Troponin I / Q000096:biosynthesis
D015415:Biomarkers; D002316:Cardiotonic Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D019210:Troponin I; D016572:Cyclosporine; C090438:(melle-4)cyclosporin; D002118:Calcium