. Administration of a CO-releasing molecule at the time of reperfusion reduces infarct size in vivo. Am J Physiol Heart Circ Physiol 286: H1649-H1653, 2004. First published January 2, 2004 10.1152/ajpheart.00971.2003.-Although carbon monoxide (CO) has traditionally been viewed as a toxic gas, increasing evidence suggests that it plays an important homeostatic and cytoprotective role. Its therapeutic use, however, is limited by the side effects associated with CO inhalation. Recently, transition metal carbonyls have been shown to be a safe and effective means of transporting and releasing CO groups in vivo. The goal of the present study was to test whether a water-soluble CO-releasing molecule, tricarbonylchloro(glycinato) ruthenium (II) (CORM-3), reduces infarct size in vivo when given in a clinically relevant manner, i.e., at the time of reperfusion. Mice were subjected to a 30-min coronary artery occlusion followed by 24 h of reperfusion and were given either CORM-3 (3.54 mg/kg as a 60-min intravenous infusion starting 5 min before reperfusion) or equivalent doses of inactive CORM-3, which does not release CO. CORM-3 had no effect on arterial blood pressure or heart rate. The region at risk did not differ in control and treated mice (44.5 Ϯ 3.5% vs. 36.5 Ϯ 1.6% of the left ventricle, respectively). However, infarct size was significantly smaller in treated mice [25.8 Ϯ 4.9% of the region at risk (n ϭ 13) vs. 47.7 Ϯ 3.8% (n ϭ 14), P Ͻ 0.05]. CORM-3 did not increase carboxyhemoglobin levels in the blood. These results suggest that a novel class of drugs, CO-releasing molecules, can be useful to limit myocardial ischemia-reperfusion injury in vivo.carbon monoxide-releasing molecules; myocardial ischemia; reperfusion injury; transition metal carbonyls MAMMALIAN TISSUES continually produce carbon monoxide (CO) as a result of the breakdown of heme by heme oxygenase (HO) (13). Although CO has been traditionally regarded as toxic, recent evidence has revealed that this gas exerts pleiotropic homeostatic effects. Specifically, CO has been shown to promote vasorelaxation (12, 17) and to inhibit proliferation of smooth muscle cells (21), apoptosis (2), transplant rejection (4), inflammation (14, 15), platelet aggregation, microvascular thrombosis (3), cytokine production (9, 18), and oxidative stress (16). CO, delivered either as a gas or via CO-releasing molecules (CORMs), has also been shown to alleviate hypoxia/ reoxygenation injury in isolated cells and ischemia-reperfusion injury in isolated hearts (4) and in the liver (1). Although the mechanism(s) underlying the cytoprotective actions of CO has not been elucidated, evidence suggests that this gas exerts some of its effects via activation of the guanylate cyclase/ cGMP pathway (10, 22) and the p38 MAPK-dependent pathway (15).In view of the mounting evidence supporting a salubrious role of CO in a variety of pathophysiological conditions, much interest has focused on harnessing the actions of this molecule for therapeutic purposes. Thus far, most studies in vivo ha...