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The MAPK family member p38 is activated in the heart after ischemia-reperfusion (I/R) injury. However, the cardioprotective vs. proapoptotic effects associated with p38 activation in the heart after I/R injury remain unresolved. Another issue to consider is that the majority of past studies have employed the rodent as a model for assessing p38's role in cardiac injury vs. protection, while the potential regulatory role in a large animal model is even more uncertain. Here we performed a parallel study in the mouse and pig to directly compare the extent of cardiac injury after I/R at baseline or with the selective p38 inhibitor SB-239063. Infusion of SB-239063 5 min before ischemia in the mouse prevented ischemiainduced p38 activation, resulting in a 25% reduction of infarct size compared with vehicle-treated animals (27.9 [+ or -] 2.9% vs. 37.5 [+ or -] 2.7%). In the pig, SB-239063 similarly inhibited myocardial p38 activation, but there was no corresponding effect on the degree of infarction injury (43.6 [+ or -] 4.0% vs. 41.4 [+ or -] 4.3%). These data suggest a difference in myocardial responsiveness to I/R between the small animal mouse model and the large animal pig model, such that p38 activation in the mouse contributes to acute cellular injury and death, while the same activation in pig has no causative effect on these parameters. signaling; kinase; infarction; heart

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 improved functional recovery seen with Bosentan., Jeffrey M. Pearl, M.D., Donald W. Thomas, C.CP., Jerri L. McNamara, C.C.P., Jenni L. Raake, R.R.T., David P. Nelson, MD, PhD. Children's Hospital Medical Center, Cincinnati, [...]

Background: Endothelin-1 has been implicated as a cause of acute pulmonary hypertension (PHTN). Inhaled nitric oxide (iNO) has emerged as frontline therapy for PHTN, including PHTN following repair of congenital heart disease. Proposed advantages of iNO include its lack of significant systemic hemodynamic effects, and its relative `safety'. However, `rebound' PHTN has been described when inhaled NO is weaned, suggesting either impaired endogenous NO production or elevated levels of vasoconstricting agents such as ET-1. ET-1 and NO are known to crosstalk, and it is possible that iNO may affect levels of ET-1. This clinical study was undertaken in order to determine the effects of inhaled NO on levels of ET-1. Methods: Group 1- Fifteen infants and children with congenital heart disease (age 3 d-23 mos) requiring iNO for post-CPB PHTN. Arterial blood was obtained prior to iNO, at several time points during, and 24 hours following cessation of inNO. Group 2 consisted of ten adult medical patients placed on iNO therapy, and Group 3 included six infants post-CPB who were at risk for PHTN but who did not require iNO. Results: In Group 1, the average increase in ET-1 levels was 48% by 12 hrs of iNO therapy (mean average values= 3.94 pg/ml vs. 2.83 pg/ml), and levels remained elevated at 48 hours. With cessation of iNO ET-1 levels decreased an average of .59 pg/ml, from 107% of baseline to 86% of baseline. In Group 2, ET-1 levels increased above baseline by an average of 44%, 61%, 51%, and 50% at 2, 12, 24, and 48 hours (mean average values= 3.25, 3.3, 3.1, and 3.0 pg/ml compared with baseline of 2.33pg/ml). Prior to cessation of iNO, ET-1 levels were 124% of baseline (2.89 pg/ml) and fell dramatically to 54% of baseline (1.26 pg/ml) within 24 hours of discontinuing iNO. In Group 3, ET-1 levels decreased by an average of 24% and 35% at 12 and 24 hours post-op. (2.29, 1.68, 1.21 pg/ml at baseline, 12, and 24 hours). Conclusion: ET-1 levels increase by as much as 61% following institution of inhaled NO therapy. The increase in ET-1 does not appear to be a result of CPB as levels did not increase in non-treated patients post-CPB, but did occur in non-surgical adult patients. These data suggest that iNO results in an increase in systemic ET-1 levels. Levels decrease back towards baseline after 48 hours, and decrease abruptly when iNO is stopped. This increase in ET-1 may explain part of the rebound phenomenon seen when attempting to wean iNO, and suggests that once iNO therapy is begun, it should be continued for at least 48 hours until ET-1 levels begin to decrease back towards baseline., Jeffrey M. Pearl, M.D., David P. Nelson, M.D., Ph.D., Jenni L. Raake, R.R.T., Peter B. Manning, M.D., Steven M. Schwartz, M.D., Thomas P. Shanley, M.D., Hector R. Wong, M.D. Children's [...]