Protection from reperfusion injury after cardiac transplantation by inhibition of adenosine metabolism and nucleotide precursor supply.
BACKGROUND
Adenosine (Ado) triggers numerous protective mechanisms in the heart that may attenuate ischemia-reperfusion injury in cardiac grafts. We aimed to establish whether sustained increase in endogenous Ado production by the combined application of Ado metabolism inhibitors and nucleotide precursors attenuates reperfusion injury in transplanted hearts.


RESULTS
Rat hearts were collected after the infusion of St Thomas' Hospital cardioplegic solution, stored at 4 degrees C for 4 hours, and heterotopically transplanted into the abdomen of recipient rats. A solution containing Ado deaminase inhibitor erythro-9(2-hydroxy-3-nonyl)adenine, Ado kinase inhibitor 5'-aminoadenosine, and nucleotide precursors adenine and ribose was administered at the time of reperfusion in the treated group, whereas saline was administered to control animals. After 1 or 24 hours, mechanical function of the transplanted hearts was evaluated in an ex vivo perfusion system followed by the determination of myocardial ATP with related metabolites and measurement of the activity of neutrophil-specific enzyme myeloperoxidase in cardiac homogenates. After 24 hours of reperfusion, maximum left ventricular developed pressure increased from 87.0+/-6.8 mm Hg (mean+/-SEM) in controls to 118.1+/-8.2 mm Hg in the treated group (P<0.05), ATP increased from 11.0+/-0.8 micromol/g dry wt in controls to 15.1+/-1.2 micromol/g dry wt in the treated group (P<0.01), and myeloperoxidase activity decreased from 2.23+/-0.60 U/g wet wt in controls to 0.58+/-0.12 U/g wet wt in the treated group (P<0.001). No differences in cardiac function, ATP, or myeloperoxidase activity were observed between the treated group and controls after 1 hour of reperfusion.


CONCLUSIONS
The administration of Ado metabolism inhibitors with nucleotide precursors causes a sustained increase in endogenous Ado production and exerts a potent protective effect against reperfusion injury in transplanted hearts. Improved cardiac function and elevated ATP concentration were accompanied by complete amelioration of neutrophil infiltration in treated hearts, suggesting that reduction in postischemic inflammation could be an important mechanism of this protective effect.
Smolenski
R T
RT
Heart Science Centre, Imperial College School of Medicine at Harefield Hospital, Harefield, Middlesex, UK. r.smolenski@ic.ac.uk
Raisky
O
O
Slominska
E M
EM
Abunasra
H
H
Kalsi
K K
KK
Jayakumar
J
J
Suzuki
K
K
Yacoub
M H
MH
D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D000241:Adenosine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000243:Adenosine Deaminase / Q000378:metabolism; D058892:Adenosine Deaminase Inhibitors; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002314:Cardioplegic Solutions / Q000494:pharmacology; D003404:Creatinine / Q000097:blood; D003839:Deoxyadenosines / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016027:Heart Transplantation / Q000379:methods*; D066298:In Vitro Techniques; D007249:Inflammation / Q000517:prevention & control; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D012266:Ribose / Q000378:metabolism / Q000494:pharmacology*; D016896:Treatment Outcome
D058892:Adenosine Deaminase Inhibitors; D002314:Cardioplegic Solutions; D003839:Deoxyadenosines; D004791:Enzyme Inhibitors; C057928:5'-amino-5'-deoxyadenosine; C010192:9-(2-hydroxy-3-nonyl)adenine; D012266:Ribose; D003404:Creatinine; D000248:Adenosine Kinase; D000243:Adenosine Deaminase; D000225:Adenine; D000241:Adenosine