Evidence for an essential role of cyclooxygenase-2 as a mediator of the late phase of ischemic preconditioning in mice

Abstract

Recent studies have demonstrated that cyclooxygenase-2 (COX-2) is an essential mediator of the cardioprotective effects of the late phase of ischemic preconditioning (PC) in rabbits. The goal of this study was to determine whether COX-2 also plays an essential role in late PC in the mouse. B6129F 2 /J mice under-went a 30-min coronary occlusion followed by 24 h of reperfusion. Administration of the COX-2 selective inhibitor, NS-398, 30 min prior to the 30-min occlusion (5 mg/kg i.p.) had no appreciable effect on infarct size compared with untreated controls (58.8 ± 2.1 %, vs. 58.8 ± 4.3 % of the risk region, respectively). When mice were preconditioned with six cycles of 4-min coronary occlusion/4-min reperfusion 24 h prior to the 30-min occlusion, infarct size was markedly reduced (19.3 ± 3.4 %), indicating a late PC effect. The protective effect of late PC was completely abrogated by administration of NS-398 30 min before the 30-min coronary occlusion (67.7 ± 3.0 %), but not by administration of vehicle alone (23.6 ± 3.7 %). These results indicate that COX-2 mediates the late phase of ischemic PC in the mouse and imply that the role of this enzyme in cardioprotection is not species-specific.

Glucocorticoid protects rodent hearts from ischemia/reperfusion injury by activating lipocalin-type prostaglandin D synthase–derived PGD2 biosynthesis

“…Notably, NS398 completely suppressed both the improvement of LV functional recovery and the reduction in LDH release into the perfusate conferred by DEX treatment ( Figure 5, A-F). As previously reported, NS398 alone does not exacerbate the degree of ischemia/reperfusion injury (19,20). …”

Administration of a CO-releasing molecule at the time of reperfusion reduces infarct size in vivo

“…86-23). The experimental preparation has been described in detail previously (7,8). Briefly, the study was performed in male ICR mice weighing 35.0 Ϯ 0.6 g (age, 9.4 Ϯ 0.3 wk).…”

“…Mice were anesthetized with pentobarbital sodium (60 mg/kg iv), intubated, and ventilated with room air supplemented with oxygen at a rate of 105 strokes/min and with a tidal volume of 0.6 ml using a small rodent ventilator. These respiratory settings result in physiological values of arterial pH (7.39 Ϯ 0.01) and adequate oxygenation (7,8). Body temperature was carefully monitored with a rectal probe and maintained as close as possible to 37.0°C.…”

“…To delineate infarcted from viable myocardium, the heart was then perfused with 1% triphenyltetrazolium chloride in phosphate buffer. To delineate the occluded/reperfused bed, the coronary artery was tied at the site of the previous occlusion and the aortic root was perfused with 10% Phthalo blue dye (7,8). As a result of this procedure, the region at risk was identified by the absence of blue dye, whereas the rest of the left ventricle (LV) was stained dark blue.…”

5-Lipoxygenase Metabolic Contributions to NSAID-Induced Organ Toxicity

“…Part of the reason for long-term ulcer complications with selective COX-2 NSAIDs may be that both COX-1 and [26,27]. In animal models of MI, the concentrations of PGs and PCs were reduced when rats and mice were administered a selective COX-2 inhibitor compared with a placebo [28].…”