15-F2t-isoprostane exacerbates myocardial ischemia-reperfusion injury of isolated rat hearts

Reactive oxygen species induce formation of 15-F-2t-isoprostane (15-F-2t-IsoP), a specific marker of in vivo lipid peroxidation, which is increased after myocardial ischemia and during the subsequent reperfusion. 15-F-2t-IsoP possesses potent bioactivity under pathophysiological conditions. However, it remains unknown whether 15-F-2t-IsoP, by itself, can influence myocardial ischemia-reperfusion injury (IRI). Adult rat hearts were perfused by the Langendorff technique with Krebs-Henseleit (KH) solution at a constant flow rate of 10 ml/min. 15-F-2t-IsoP (100 nM), SQ-29548 (1 mu M, SQ), a thromboxane receptor antagonist that can abolish the vasoconstrictor effect of 15-F-2t-IsoP, 15-F-2t-IsoP+SQ in KH, or KH alone (vehicle control) was applied for 10 min before induction of 40 min of global ischemia followed by 60 min of reperfusion. During ischemia, saline (control), 15-F-2t-IsoP, 15-F-2t-IsoP+SQ, or SQ in saline was perfused through the aorta at 60 mu l/min. 15-F-2t-IsoP, 15-F-2t-IsoP+SQ, or SQ in KH was infused during the first 15 min of reperfusion. Coronary effluent endothelin-1 concentrations were significantly higher in the group treated with 15-F-2t-IsoP than in the control group during ischemia and also in the later phase of reperfusion (P<0.05). Infusion of 15-F-2t-IsoP increased release of cardiac-specific creatine kinase, reduced cardiac contractility during reperfusion, and increased myocardial infarct size relative to the control group. SQ abolished the deleterious effects of 15-F-2t-IsoP. 15-F-2t-IsoP exacerbates myocardial IRI and may, therefore, act as a mediator of IRI. 15-F-2t-IsoP-induced endothelin-1 production during cardiac reperfusion may represent a mechanism underlying the deleterious actions of 15-F-2t-IsoP.