Brief antecedent ischemia enhances recombinant tissue plasminogen activator-induced coronary thrombolysis by adenosine-mediated mechanism

Background-Clinical studies have implicated preinfarct angina (brief antece dent ischemia/reperfusion [I/R]) as a predictor of more rapid thrombolysis and lower rates of reocclusion. However, the effects of antecedent ischemia on the efficacy of thrombolysis have not been rigorously assessed. Using a canine model of coronary thrombosis, we aimed to (1) reproduce these clini cal findings and (2) determine whether release of adenosine (a potent inhib itor of platelet aggregation via stimulation of platelet A(2) receptors) du ring brief I/R contributes to this improved patency. Methods and Results-To address our first objective, we compared the time re quired to achieve lysis with recombinant tissue plasminogen activator and p atency during the first 2 hours after lysis in does in which 1-hour thrombo tic occlusion was preceded by brief I/R (10-minute coronary occlusion/10-mi nute reperfusion) versus 20-minute uninterrupted perfusion (controls). Time to lysis was accelerated in the VR group versus the control group (11 +/- 1 versus 35 +/- 6 minutes, P=0.004). In addition, the duration of subsequen t reocclusion was reduced (17 +/- 12 versus 30 +/- 11 minutes), and the are a of the flow-time profile (normalized to baseline flow x 120 minutes) was increased (64 +/- 12% versus 35 +/- 7%, P=0.04) in the I/R cohort. The prot ocol was then repeated, but all dogs were pretreated with the adenosine A(2 )/A(1) antagonist CGS 15933 (CGS, 1.5 mg/kg). Time to lysis (38 versus 39 m inutes) and subsequent patency were comparable in the CGS+control group ver sus the CGS+I/R group. Conclusions-Brief antecedent I/R enhances the efficacy of coronary thrombol ysis in this canine model, which is due, at least in part, to an adenosine- mediated mechanism.