Thromboxane A2 in preservation-reperfusion injury: the effect of thromboxane A2 synthetase inhibitor.
It has been suggested that thromboxane A2 (TXA) plays important roles in preservation/reperfusion organ injury. In this report, we investigated the prostanoid release from the liver and the effect of a selective TXA synthetase inhibitor (E)-3-[p-(1H-imidazol-yl-methyl)-phenyl]-2-propenoic acid, OKY046) during cold preservation and after reperfusion. Rat livers were preserved in lactated Ringer's solution at 4 degrees C for 2, 4, and 6 hr and perfused with oxygenated Krebs-Henseleit buffer using recirculating perfusion system, and prostanoids were measured during cold preservation and after reperfusion. OKY046 and a novel TXA receptor antagonist [(9,11), (11,12)-Dideoxa-9a, 11a-dimethyl-methano-11,12-methano-13,14-dihydro-13-aza-14-oxo-15-cyclo pentyl-16,17,18,19,20-pentanor-15-epi-TXA, ONO3708] were added into the preservation solution and perfusate. Along with the preservation time, both the production and release of TXA was observed to increase; however, almost all the produced TXA was stored in the liver tissue. Afterwards, the stored TXA was released into perfusate in 15 min after reperfusion. OKY046 significantly decreased both the production and release of TXA. In addition, OKY046 improved the histological damage and trypan blue uptake of liver cells. Our results demonstrate that TXA, stored in the liver during preservation, might therefore be a potential trigger of reperfusion injury, and as a result, OKY046 reduces reperfusion injury by decreasing the production of TXA during preservation.
Suehiro
T
T
Department of Surgery II, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Yanaga
K
K
Itasaka
H
H
Kishikawa
K
K
Shirbe
K
K
Shimada
M
M
Sugimachi
K
K
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D003080:Cold Temperature; D004727:Endothelium / Q000166:cytology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000502:physiology*; D008689:Methacrylates / Q000494:pharmacology*; D009926:Organ Preservation / Q000379:methods*; D009929:Organ Size / Q000187:drug effects; D010741:Phospholipases A / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000503:physiopathology*; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D013929:Thromboxane B2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D008689:Methacrylates; D017482:Receptors, Thromboxane; D016718:Arachidonic Acid; D013929:Thromboxane B2; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; C049855:ONO 3708; D010741:Phospholipases A; D013930:Thromboxane-A Synthase; C034364:ozagrel