Inhibition of mitochondrial permeability transition to prevent the post-cardiac arrest syndrome: a pre-clinical study

• DOI: 10.1093/eurheartj/ehq112
• Publication Date: 2010-04-30T00:30:10Z
• Authors: M. Cour; J. Loufouat; M. Paillard; L. Augeul; J. Goudable; M. Ovize; L. Argaud
• Keywords: Male; Cardiotonic Agents; Mitochondrial Permeability Transition Pore; Cell Respiration; Troponin I; Hemodynamics; Myocardial Reperfusion Injury; Mitochondrial Membrane Transport Proteins; Myocardial Contraction; Cardiopulmonary Resuscitation; [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system; Heart Arrest; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Cyclosporine; Animals; Calcium; Rabbits; Ischemic Postconditioning; Biomarkers

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.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).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.