ENDOTHELIN-1 BLOCKADE WITH BOSENTAN DECREASES POST-REOXYGENATION VENTRICULAR DYSFUNCTION AND LEUKOCYTE-MEDIATED INJURY

Background: Reoxygenation of hypoxic myocardium during repair of congenital heart defects results in leukocyte-mediated injury and poor ventricular function. Endothelin-1 (ET-1) which is increased under conditions of hypoxia is a potent vasoconstrictor, directly depresses myocardial function, and stimulates leukocyte adhesion and activation. In order to determine if ET-1 blockade improves post-reoxygenation ventricular function and decreases leukocyte-mediated injury neonatal piglets were studied. Methods: Following instrumentation and baseline measurements, 14 open-chest piglets underwent 90 minutes of ventilator hypoxia (FIO2=.12), one hour of reoxygenation on cardiopulmonary bypass, and two hours of recovery (Group 1). An additional 9 animals undergoing an identical protocol received an infusion of Bosentan (5mg/kg/hr) during hypoxia and reoxygenation (Group 2). Systolic ventricular function (+dp/dt) was determined. LV myocardium was analyzed at end-recovery for myeloperoxidase (MPO) activity and lipid peroxidase activity (LPO). Results: In Group 1, RV dp/dt increased to 148% of baseline (533 vs. 369) during hypoxia, but fell to 78% of baseline following reoxygenation (281 vs. 360, p [is less than] .05). LV dp/dt decreased to 80% of baseline by end-hypoxia (994 vs. 1242, p [is less than] .05) and following reoxygenation decreased to 52% of baseline (646 vs. 1242, p [is less than] .005). In contrast, Group 2 animals had complete preservation of RV dp/dt (102% of baseline) at end-recovery. In Group 2, LV dp/dr was significantly less depressed at end-recovery than in Group 1 (74% of baseline). LV dp/dt at end-recovery was significantly greater (p [is less than] .05) in Group 2 than in Group 1 (903 vs. 646). Group 2 had significantly lower (p [is less than] .05) myocardial tissue MPO than Group 1; LV MPO in mU/50 mg tissue was 80.9 in group 1, 21.7 in Group 2, and 13.1 in control hearts. LV LPO in nM/100 mg wet tissue was also significantly lower in Group 2 (p [is less than] .05) than in Group 1 at end-recovery; 4.6 in Group 1, 3.5 in Group 2, and 3.0 in control hearts. Conclusions: Reoxygenation of hypoxic myocardium results in leukocyte-mediated injury and decreased ventricular function. Increased levels of ET-1 during hypoxia may contribute to reoxygenation injury. ET-1 blockade with Bosentan decreases myocardial leukocyte activity as evidenced by lower MPO and LPO values. This decrease in leukocyte mediated reoxygenation injury may account for the impro