Adenosine receptor involvement in a delayed phase of myocardial protection 24 hours after ischemic preconditioning.

Abstract

BACKGROUND We previously reported a delayed phase of protection against infarction 24 hours after ischemic preconditioning in the rabbit. In the present study, we investigated the possibility that this "second window of protection," like the well-described early phase of protection in the rabbit, might be associated with adenosine receptor activation. METHODS AND RESULTS In the first series of experiments, we examined whether adenosine receptor blockade with 8-(p-sulfophenyl)-theophylline (SPT) during preconditioning could abolish the delayed protection against infarction 24 hours later. Open-chest rabbits were subjected to myocardial preconditioning (PC) with the four 5-minute coronary occlusions or they were sham operated on (SHAM). During these procedures, animals received either SPT (PC + SPT, n = 6; and SHAM + SPT, n = 6) or vehicle (PC + VEH, n = 12; and SHAM + VEH, n = 11). Twenty-four hours later, infarct development after a 30-minute coronary occlusion/120-minute reperfusion insult was assessed with triphenyltetrazolium staining. In vehicle-treated rabbits, the infarct-to-risk ratio (I/R) was reduced from 53.6 +/- 5.7% (SHAM + VEH) to 32.9 +/- 4.6% (PC + VEH) (P < .05), clearly indicating a delayed phase of protection. Although I/R was not significantly different between SHAM + VEH (53.6 +/- 5.7%) and SHAM + SPT (61.7 +/- 5.4%), in PC + SPT the delayed protection was abolished (I/R = 56.8 +/- 3.8%). In the second series of experiments, we examined if pharmacological adenosine A1 receptor stimulation could evoke a delayed phase of protection. Conscious rabbits were pretreated with intravenous boluses of saline or the A1 receptor-selective agonist 2-chloro-N6-cyclopentyladenosine (CCPA), and infarct size in response to 30-minute ischemia/120-minute reperfusion was assessed 24 hours later. I/R was 54.5 +/- 2.7% in saline-pretreated controls (n = 12). Pretreatment with 25 micrograms/kg CCPA (n = 6), 50 micrograms/kg CCPA (n = 6), or 100 micrograms/kg CCPA (n = 6) resulted in I/R ratios of 37.1 +/- 4.2% (P < .01), 37.7 +/- 2.2% (P < .01), and 26.3 +/- 5.7% (P < .01), respectively. In both series of experiments, there were no differences in systemic hemodynamics during the infarct protocol, assessed as rate-pressure product, between the different experimental groups. CONCLUSIONS Twenty-four hours after repetitive brief coronary occlusions, susceptibility to infarction in rabbit myocardium is reduced, an effect that may have clinical relevance. Results of the present study suggest that this second window of protection following preconditioning may, like the early phase of protection, be initiated by an adenosine-related mechanism.