Evidence that S-adenosyl-L-methionine diastereoisomers may reduce ischaemia-reperfusion injury by interacting with purinoceptors in isolated rat liver.
1. Mechanisms underlying the haemodynamic activity of diastereoisomers of S-adenosyl-L-methionine (SAM) were investigated using inhibitors of purinoceptors and nitric oxide (NO) synthase in perfused rat livers damaged by sequential 24 h cold and 20 min rewarming ischaemia + reperfusion. 2. Stored livers were flushed with 10 ml saline alone (control) or with added (R,S) or (S,S) SAM (100 microM) and reperfused in the absence (control) or presence of 10 microM 8-phenyltheophylline (8-PT) or 100 microM L-N-monomethylarginine (L-NMMA). 3. Both SAM diastereoisomers rapidly increased blood flow and bile production versus controls (P<0.001) but the (R,S) isomer induced greater increases in blood flow and the (S,S) isomer greater increases in bile production: 625 versus 596 versus 518 ml blood flow and 100 versus 119 versus 56 mg bile production per g liver over 3 h in (R,S), (S,S) and control, respectively. 4. 8-PT prevented the enhancement of blood flow by (S,S) SAM (529 versus 596 ml g(-1) liver over 3 h for (S,S) SAM alone, P<0.001), but was without effect in control livers. 8-PT also reduced SAM-enhanced bile production: 51 versus 119 mg g(-1) liver over 3 h, P<0.001. L-NMMA reduced blood flow and bile production similarly in the absence or presence of (S,S) SAM. 5. Thus, SAM may improve liver perfusion after ischaemia-reperfusion injury via stimulation of P, (A2) purinoceptors at which SAM shows activity. The choleretic activity of (S,S) SAM is disproportionately greater than enhanced blood flow and may occur independently of a NO-dependent component of bile production.
Dunne
J B
JB
Institute of Liver Studies, Academic Department of Surgery, King's College Hospital and School of Medicine and Dentistry, London.
Alexander
B
B
Williams
R
R
Tredger
J M
JM
D000818:Animals; D001646:Bile / Q000378:metabolism; D001783:Blood Flow Velocity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000187:drug effects*; D008297:Male; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption; D058914:Purinergic Antagonists; D051381:Rats; D011917:Rats, Inbred Lew; D011983:Receptors, Purinergic / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control*; D012436:S-Adenosylmethionine / Q000737:chemistry / Q000627:therapeutic use*; D013237:Stereoisomerism; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D058914:Purinergic Antagonists; D011983:Receptors, Purinergic; D019323:omega-N-Methylarginine; D019344:Lactic Acid; D012436:S-Adenosylmethionine; D013806:Theophylline; C028322:8-phenyltheophylline; D005947:Glucose; D010100:Oxygen