Effects of P38 mitogen-activated protein kinase inhibitor as an additive to celsior solution on canine heart transplantation from non-heart-beating donors

Abstract

Background: The activation of p38 mitogen-activated protein kinase (MAPK) plays an important role on ischemia/reperfusion injury. FR167653 is a novel p38 MAPK inhibitor. This study evaluated the effects of p38 MAPK inhibition using FR167653 as an additive to the Celsior solution in canine heart transplantation from non-heart-beating donors (NHBDs).Methods: Donor hearts were left in situ for 20 min after cardiac arrest induced by rapid exsanguination. Twelve donor-recipient pairs of mongrel dogs were divided into two groups, the control and FR group (n = 6 each). Both group animals underwent coronary flushing and were immersed into the Celsior solution with or without FR167653 for 4 hr. Orthotopic heart transplantation was then performed. Cardiac output (CO), left ventricular pressure (LVP) and end-systolic maximal elastance (Emax) were measured at 1 and 2 hr after weaning from cardiopulmonary bypass (CPB), and then grafts were harvested for histopathological study. The activation of MAPKs including p38 MAPK, c-Jun N-terminal protein kinase (JNK) and extracellular signal-regulated protein kinase (ERK) were evaluated by the use of other 12 mongrel dogs during the heart transplantation procedure.Results: CO and LVP recovery rates and Emax were significantly (p < 0.05) higher in the FR group than in the control group 2 hr after weaning from CPB. Histopathological damage was more severe in the control group. The p38 MAPK, JNK and ERK were significantly (p < 0.05) activated in the control group after reperfusion. The p38 MAPK activation was significantly (p < 0.05) inhibited in the FR group than in the control group 10 min after reperfusion.Conclusions: The addition of FR167653 to the Celsior solution improved graft viability which might be due to the inhibition of p38 MAPK activation after transplantation, and may attenuate ischemia/reperfusion injury in heart transplantation from NHBDs.