Isoflurane induces substrate‐dependent early mitochondrial PTP opening (648.13)

Abstract

The volatile anesthetic isoflurane (ISO) may increase permeability of mitochondria to protect against mitochondrial injury. Prolonged opening of the mitochondrial permeability transition pore (mPTP) inevitably causes mitochondrial demise, whereas transient mPTP opening may release accumulated Ca2+ from the matrix to avoid subsequent irreversible mPTP opening due to Ca2+ overload. To test if ISO alters mPTP opening, we isolated mitochondria from Wistar rat hearts to assess buffer Ca2+ uptake by Fura 4F. We found that: (a) ISO (1 mM) induced earlier mPTP opening by increasing Ca2+ uptake rate with succinate (SUC). (b) ISO did not alter mPTP opening but reduced Ca2+ uptake with pyruvate/malate. (c) 10 µM ryanodine or 10 nM imperatoxin A with SUC increased Ca2+ uptake and induced earlier mPTP opening; this suggests that ISO’s effects on mPTP may be due to increased conductance via mitochondrial ryanodine receptors (mRyR). We have patch‐clamped single mRyRs in mitoplasts. Our data infer indirectly that SUC substrate ‐dependent transient mPTP opening may be due to enhanced RyR Ca2+ uptake. Transient Ca2+ release could be a mechanism underlying ISO –induced cardiac protection in ischemia‐reperfusion injury.Grant Funding Source: P01‐GM066730, R01‐HL095122, R01‐HL089514