Bosentan affects 15-F2t-isoprostane adverse effects on postischemic rat hearts

15-F(2t)-isoprostane (IsoP), a marker of reactive oxygen species-induced oxidative stress, is increased after myocardial ischemia and reperfusion. It exerts deleterious effects on postischemic myocardium accompanied with increased release of endothelin-1 (ET-1), a potent vasoconstrictor. We hypothesized that IsoP exacerbates myocardial ischemia-reperfusion injury by stimulating ET-1 production, and that ET-1 blockade can attenuate or prevent these deleterious effects of IsoP.

Adult rat hearts were perfused by the Langendorff technique with Krebs-Henseleit solution (KH) at a constant flow rate of 10 mL/min. Global myocardial ischemia was induced by stopping KH perfusion for 40 min followed by 60 min of reperfusion. Hearts were randomized to one of the five groups (n = 8 each): untreated control, treated with IsoP (100 nM), or the ET-1 receptor A/B antagonist bosentan (1 μM) alone or in combination 10 min prior to, during 40 min global ischemia and 15 min of reperfusion, or treated with IsoP as above plus delayed administration of bosentan after 15 min of reperfusion.

Coronary effluent ET-1 concentrations in the IsoP group were higher than those in the control group during ischemia and reperfusion (P < 0.05), which was associated with increased release of cardiac-specific creatine kinase, reduced cardiac contractility during reperfusion, and increased myocardial infarct size (all P < 0.05 versus control). Bosentan administration during early reperfusion exacerbated the IsoP deleterious effects, while delayed administration attenuated it.

15-F(2t)-isoprostane-induced ET-1 production during later reperfusion is detrimental to functional recovery of damaged myocardium, while ET-1 increase during early reperfusion seems to improve it.