© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Protection of hearts from reperfusion injury by propofol is associated with inhibition of the mitochondrial permeability transition
aAzerbaijan Medical University, Bakykhanov Str., Baku, Azerbaijan
bBristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Bristol, UK
cDepartment of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada
dDepartment of Biochemistry, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK
* Corresponding author. Tel.: +44-117-928-8592; fax: +44-117-928-8274 a.halestrap{at}bristol.ac.uk
Objective: Diminishing oxidative stress may protect the heart against ischaemia–reperfusion injury by preventing opening of the mitochondrial permeability transition (MPT) pore. The general anaesthetic agent propofol, a free radical scavenger, has been investigated for its effect on the MPT and its cardioprotective action following global and cardioplegic ischaemic arrest. Method: Isolated perfused Wistar rat hearts were subjected to either warm global ischaemia (Langendorff) or cold St. Thomas’ cardioplegia (working heart mode) in the presence or absence of propofol. MPT pore opening was determined using [3H]-2-deoxyglucose-6-phosphate ([3H]-DOG-6P) entrapment. The respiratory function of isolated mitochondria was also determined for evidence of oxidative stress. Results: Propofol (2 µg/ml) significantly improved the functional recovery of Langendorff hearts on reperfusion (left ventricular developed pressure from 28.4±6.2 to 53.3±7.3 mmHg and left ventricular end diastolic pressure from 52.9±4.3 to 37.5±3.9 mmHg). Recovery was also improved in propofol (4 µg/ml) treated working hearts following cold cardioplegic arrest. External cardiac work on reperfusion improved from 0.42±0.05 to 0.60±0.03 J/s, representing 45–64% of baseline values, when compared to controls (P<0.05). Propofol inhibited MPT pore opening during reperfusion, [3H]-DOG-6P entrapment being 16.7 vs. 22.5 ratio units in controls (P<0.05). Mitochondria isolated from non-ischaemic, propofol-treated hearts exhibited increased respiratory chain activity and were less sensitive to calcium-induced MPT pore opening. Conclusion: Propofol confers significant protection against global normothermic ischaemia and during cold cardioplegic arrest. This effect is associated with less opening of mitochondrial MPT pores, probably as a result of diminished oxidative stress. Propofol may be a useful adjunct to cardioplegic solutions in heart surgery.
KEYWORDS AF, aortic flow-rate; AP, peak aortic pressure; CF, coronary flow-rate; CO, cardiac output; DOG, 2-deoxyglucose; DOG-6P, 2-deoxyglucose-6-phosphate; ECW, external cardiac work; EGTA, ethylene glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraacetic acid; HR, heart rate; KHS, Krebs–Henseleit solution; LAP, left ‘atrial’ pressure; LVDP, left ventricular developed pressure; LVEDP, left ventricular end diastolic pressure; MPT, mitochondrial permeability transition; NTA, nitrilotriacetic acid; TMPD, N,N,N',N'-tetramethyl-p-phenylendiamine; RPP, rate-pressure product
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