Administration of a CO-releasing molecule induces late preconditioning against myocardial infarction

Mounting evidence suggests that carbon monoxide (CO) exerts powerful cytoprotective actions. CO-releasing molecules (CORMs) offer an effective means of delivering CO to tissues in vivo. The goal of the present study was to determine whether a water-soluble CORM, tricarbonylchloro(glycinato) ruthenium(II) (CORM-3), induces delayed protection against myocardial infarction 24:h later and to explore the duration of this protection. Mice received a 60-min i.v. infusion of CORM-3 or inactive CORM-3 (which does not release CO) and then, 24, 72, or 120:h later, underwent a 30-min coronary occlusion followed by 24:h of reperfusion. Pretreatment with CORM-3 24:h prior to coronary occlusion markedly reduced infarct size (24.8% ± 2.9% of the risk region vs. 43.8% ± 4.4% with inactive CORM-3). The infarct-sparing effect of CORM-3 was still evident 72:h after administration of the CO donor (20.4% ± 3.7% of the risk region vs. 41.9% ± 2.5% with inactive CORM-3) but was no longer apparent at 120:h. Both at 24 and 72:h, the protective effects of CORM-3 were equivalent to those afforded by the late phase of ischemic preconditioning (PC; 27.0% ± 2.9% and 30.3% ± 3.9% of the risk region, respectively). We conclude that the novel CO-releasing compound, CORM-3, induces delayed protection against myocardial infarction which is similar to that afforded by the late phase of ischemic PC, and that this salubrious effect is sustained for 72:h. To our knowledge, this is the first report that exposure to CO causes the heart to shift to a preconditioned phenotype. In addition, this study provides the first evidence that the cardioprotective actions of ischemic PC persist for 72:h in the mouse.