(Circulation. 2000;101:2841.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Adenosine A1 Receptor Activation Induces Delayed Preconditioning in Rats Mediated by Manganese Superoxide Dismutase
From The Hatter Institute and Centre for Cardiology, University College London Hospitals and Medical School, London, UK.
Correspondence to Professor D.M. Yellon, The Hatter Institute and Centre for Cardiology, University College London Hospitals and Medical School, Grafton Way, London WC1E 6DB, UK. E-mail hatter-institute{at}ucl.ac.uk
Background—We have previously described a second window of protection against infarction in rabbits 24 to 72 hours after adenosine A1 receptor (A1R) activation. In this study, we examined the potential role of the mitochondrial antioxidant manganese superoxide dismutase (Mn-SOD) as a potential end effector in mediating this protection.
Methods and Results—Rats were treated with an intravenous bolus of the A1R agonist 2-chloro-N6-cyclopentyladenosine (CCPA, 75 µg/kg) or saline vehicle. They were also given a 5 mg/kg IV infusion of a 22-mer phosphorothioate oligodeoxynucleotide (ODN) with sequence antisense to the initiation site of rat Mn-SOD mRNA. Sense ODN and scrambled ODN were used as controls. Twenty-four hours later, hearts were isolated and perfused with buffer at constant pressure and subjected to 35 minutes of regional ischemia and 2 hours of reperfusion. Treatment with CCPA compared with saline vehicle (control) significantly reduced infarct size, expressed as percentage of myocardium at risk (22.3±3.3% versus 42.1±3.8%, respectively; P=0.001). This protection was completely abolished by prior treatment with antisense ODN, which had no effect on its own. Neither sense ODN nor scrambled ODN had an effect on the CCPA-induced delayed cardioprotection. In separate animals, 24 hours after the same treatment, hearts were assayed for Mn-SOD content and activity. CCPA treatment induced a significant increase in myocardial Mn-SOD content and activity compared with the control condition; this increase was abolished by pretreatment with antisense ODN.
Conclusions—This is the first study to show that transient A1R activation induces delayed cardioprotection in the rat. These results strongly suggest an important role for mitochondrial Mn-SOD as a potential end effector of this protection.
Key Words: adenosine • myocardial infarction • superoxide dismutase
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