Abstract 213: The Late Phase of Ischemic Preconditioning Is Abrogated by a Specific Prostaglandin I2 Receptor Antagonist
Previous studies have shown that cyclooxygenase-2 (COX-2) mediates the late phase of ischemic preconditioning (PC) by producing various cardioprotective prostanoids including prostacyclin (PGI2) and prostaglandin (PG) E2 (PGE2). Prostanoids are known to act via activation of specific receptors. However, the specific PG receptors responsible for the salubrious actions of COX-2 in PC and myocardial ischemia/reperfusion injury remain unclear. The PGI2 receptor (IP) mediates the actions of PGI2 and PGE2, the two major COX-2-derived prostanoids with cardioprotective properties. Accordingly, the goal of this study was to determine the role of the IP in late PC. C57BL/6 mice underwent a 30-min coronary occlusion (O) followed by 24 h of reperfusion (R). Administration of the IP receptor selective antagonist, RO 3244794 (group III, 10 mg/kg i.p.), 30 min prior to the 30-min O had no appreciable effect on infarct size compared with untreated and vehicle-treated groups (68.4 ± 1.2 % vs. 63.3 ± 3.1 % and 65.6 ± 3.9 % of the risk region, respectively). When mice were preconditioned with six cycles of 4-min O/4-min R 24 h prior to the 30-min O, infarct size was markedly reduced (group IV, 33.2 ± 2.9 %), indicating a late PC effect. In the vehicle-treated late PC group, infarct size (group V, 37.2 ± 4.9 %) was similar to the late PC group, indicating the vehicle had no effect. However, the protective effect of late PC was completely abrogated by administration of RO 3244794 30 min before the 30-min O (group VI, 63.8 ± 4.5 %). We conclude that the IP receptor is an obligatory mediator of the late phase of ischemic PC in vivo, suggesting that pharmacologic manipulations of this receptor may be therapeutically useful.