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

Eur Heart J. 2011 Jan;32(2):226-35. doi: 10.1093/eurheartj/ehq112. Epub 2010 Apr 28.

Abstract

Aims: 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.

Methods and 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).

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Calcium / metabolism
  • Cardiopulmonary Resuscitation
  • Cardiotonic Agents / pharmacology*
  • Cell Respiration / physiology
  • Cyclosporine / pharmacology*
  • Heart Arrest / physiopathology
  • Heart Arrest / prevention & control*
  • Hemodynamics / physiology
  • Ischemic Postconditioning / methods
  • Male
  • Mitochondrial Membrane Transport Proteins / drug effects*
  • Mitochondrial Permeability Transition Pore
  • Myocardial Contraction
  • Myocardial Reperfusion Injury / physiopathology
  • Myocardial Reperfusion Injury / prevention & control
  • Rabbits
  • Troponin I / biosynthesis

Substances

  • Biomarkers
  • Cardiotonic Agents
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Troponin I
  • Cyclosporine
  • (melle-4)cyclosporin
  • Calcium