Treatment of experimental ischemia/reperfusion injury with S-adenyosylmethionine: evidence that donor pretreatment complements other regimens.
Triple therapy with S-adenosylmethionine (SAM) (given to the donor animal, included in University of Wisconsin solution [UW], and added to the reperfusing medium) has been shown to reduce the sequential cold and warm ischemia/reperfusion injuries characteristic of the liver transplantation procedure. To clarify the actions of SAM during different stages of ischemia/ reperfusion, we have compared its benefit in five dosage regimens, using perfused rat livers after sequential periods of 24 hr cold and 20 min rewarming ischemia. When added only to UW, the presence of SAM throughout ischemia improved hepatic blood flow by 26% after 15 min of reperfusion versus no treatment (2.32+/-0.18 vs. 1.84+/-0.11 ml/min/g liver, P<0.05). SAM also improved blood flow by 23% during the 3-hr perfusion overall (P<0.05). Oxygen consumption and the release of purine nucleoside phosphorylase (PNP) were decreased (both P<0.05). When added to both UW and the perfusate, SAM additionally increased bile production at 15 min (7.14+/-1.21 vs. 2.31+/-0.74 mg/h/g liver, P<0.01). By pretreating the liver donor with SAM in vivo, and including it in the preservation and reperfusing media, it was possible to prolong and amplify the benefits on blood flow (P<0.001) and bile production (P<0.05) and to sustain glucose uptake (P<0.01). An acute exposure to SAM, when used in saline to flush UW from the graft before reperfusion, increased blood flow at 15 min (by 68%) and over a 3-hr period (both P<0.001), but no indices of metabolic activity were improved. Oxygen consumption and PNP release were both decreased (P<0.05). When added to the perfusate (present throughout reperfusion), SAM increased blood flow at 15 min (58%) and over a 3-hr period (P<0.01 in both cases). Net glucose uptake was increased (P<0.05), whereas oxygen consumption (P<0.001) and PNP release fell (P<0.05). Actions of SAM achieved acutely and over the intermediate- and long-term all seem to underlie its benefits in reducing ischemia/reperfusion injuries.
Dunne
J B
JB
Institute of Liver Studies, King's College Hospital, London, England.
Piratvisuth
T
T
Williams
R
R
Tredger
J M
JM
D000241:Adenosine / Q000494:pharmacology; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001646:Bile / Q000378:metabolism; D005978:Glutathione / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007511:Ischemia / Q000188:drug therapy*; D008099:Liver / Q000098:blood supply*; D016031:Liver Transplantation; D008297:Male; D019188:Organ Preservation Solutions; D011887:Raffinose / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000188:drug therapy*; D012436:S-Adenosylmethionine / Q000627:therapeutic use*
D007328:Insulin; D019188:Organ Preservation Solutions; C055206:University of Wisconsin-lactobionate solution; D000493:Allopurinol; D012436:S-Adenosylmethionine; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose