Delayed or second window preconditioning induced by adenosine al receptor activation is independent of early generation of nitric oxide or late induction of inducible nitric oxide synthase

Transient adenosine A(1) receptor (A(1)R) activation induces a second windo w or delayed preconditioning against myocardial infarction 24-72 h later. E arly generation of nitric oxide and delayed induction of nitric oxide synth ase have been implicated in mediating delayed cardioprotection after ischem ic preconditioning in rabbits. Recent evidence indicates that some of the r egulatory roles of adenosine in cardiac tissue may be mediated by A,R-induc ed generation of nitric oxide. This study examined the role of nitric oxide in the mediation of A,R-induced delayed preconditioning against infarction . Pharmacologic preconditioning of rabbits with the selective A(1)R agonist 2-chloro-N-6-cyclopentyladenosine 100 mug/kg (CCPA) significantly reduced myocardial infarct size compared with control animals, after 30 min regiona l ischemia and 2 h reperfusion in vivo 24 h later (27.3 +/-4.7 vs. 46.0 +/- 3.7%, respectively: p = 0.001). Nonselective inhibition of nitric oxide syn thase with N-G-nitro-L-arginine methyl ester(10 mg/kg) before administratio n of CCPA did not affect this infarct limitation at 24 h. Selective inhibit ion of inducible nitric oxide synthase before the prolonged ischemic insult on day 2, with two structurally independent inducible nitric oxide synthas e inhibitors, L-N-6-(1-iminoethyl)-lysine (10 mg/kg) or aminoguanidine (300 mg/kg), did not abrogate the reduction in infarction observed by pharmacol ogic preconditioning with CCPA 24 h earlier. These results suggest that the second window or delayed protection against myocardial infarction observed 24 h after pharmacologic preconditioning with an adenosine A, agonist occu rs independently of either early generation of nitric oxide or subacute ind uction of inducible nitric oxide synthase.