Protection of cardiomyocyte function by propofol during simulated ischemia is associated with a direct action to reduce pro-oxidant activity.
To demonstrate a direct protective effect of propofol on myocardial contractile performance during an ischemic episode and investigate underlying mechanisms, isolated adult rat ventricular cardiomyocytes were subjected for 2 h to (i) ischemic medium containing 2-deoxyglucose (20 mM), gassed with 100% N(2) at pH 6.4, (ii) normal medium with 95% O(2)/5% CO(2) at pH 7.4 or (iii) normal medium with addition of H(2)O(2) (50 microM). Propofol under normal conditions decreased the peak amplitude of electrically stimulated contraction of cardiomyocytes from a basal value of 6.5+/-0.37 microm to a maximum attenuation ( approximately 37%) at 0.44 to 56 microM. Under ischemic conditions, the contraction amplitude at baseline was 2.8+/-0.34 microm, but propofol, despite having a cardiodepressant effect per se, stimulated contraction, such that at >or=0.44 microM, normal and ischemic values in the presence of propofol were similar. Comparably, pro-oxidant (H(2)O(2))-induced attenuation of cell shortening was reversed by propofol (0.5 microM) to the level of contractile activity produced by the anaesthetic alone. The protective effect against ischemia-induced injury was not reflected in an improved ATP/ADP ratio nor was it mediated through diltiazem-sensitive L-type Ca(2+) channels. Propofol (0.5 microM) did, however, attenuate the ischemia- and H(2)O(2)-induced increases in the membrane lipid hydroperoxides, MDA (by 83% and 30%) and 4-HNE (by 47% and 69%). It is concluded that propofol, at clinically relevant concentrations, can counteract the effects of increased production of free radical compounds by cardiomyocytes subjected to oxidant stress and improve contractile performance.
McDermott
Barbara J
BJ
Therapeutics and Pharmacology, Queen's University Belfast, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK. b.mcdermott@qub.ac.uk <b.mcdermott@qub.ac.uk>
McWilliams
Stewart
S
Smyth
Karen
K
Kelso
Elizabeth J
EJ
Spiers
J Paul
JP
Zhao
YouYou
Y
Bell
David
D
Mirakhur
Rajinder K
RK
D000818:Animals; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010710:Phosphates / Q000378:metabolism; D015742:Propofol / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism
D010710:Phosphates; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D015742:Propofol