Abstract 3314: Opening of the Mitochondrial Permeability Transition Pore is Not Precluded With Cyclosporine A in vivo During Cardiac Arrest
Objective: A mechanism of mitochondrial injury during ischemia/reperfusion is Ca2+-induced opening of the mitochondrial permeability transition pore (mPTP). We examined whether cyclosporine A (CsA), an mPTP inhibitor, could benefit resuscitation in a rat model of cardiac arrest. We also assessed whether CsA prevents Ca2+ mediated mPTP opening in isolated mitochondria using a swelling assay.
Methods: VF was induced and left untreated for 10 mins. Resuscitation was attempted by 8 mins of chest compression and defibrillation, observing the rats for 360 mins post-resuscitation (PR). Rats were randomized to receive 10 mg/kg CsA (n=6) or vehicle (n=3) before inducing VF or 10 mg/kg CsA (n=6) or vehicle (n=3) before starting chest compression. CsA treated and vehicle treated subgroups were pooled for the analysis. Four rats not subjected to cardiac arrest served as sham. Mitochondrial NAD+ levels in hearts harvested after the PR interval served as indirect marker of mPTP opening. Mitochondria isolated from the left ventricle were suspended in assay buffer and incubated with 1 μM CsA, 250 μM CaCl2, 1 μM CsA + 250 μM CaCl2 and swelling (absorbance at 540 nm) measured relative to control (untreated).
Results: CsA had no effects on resuscitability and PR hemodynamic and myocardial function. Post-resuscitation mitochondrial NAD+ levels were ~34% lower than in sham hearts (p<0.001) but not different between groups (Figure⇓). In isolated mitochondria, CsA inhibited Ca2+ mediated mPTP opening (Figure⇓).
Conclusion: These data suggest that mitochondrial injury during cardiac arrest and resuscitation leading to mPTP opening is not prevented in vivo by CsA.