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Title: Inhibition of cyclooxygenase-2 improves cardiac function following long-term preservation.
Author: Oshima K, Takeyoshi I, Tsutsumi H, Mohara J, Ohki S, Koike N, Nameki T, Matsumoto K, Morishita Y.
Journal: J Surg Res; 2006 Oct; 135(2):380-4. PubMed ID: 16713604.
Abstract:
BACKGROUND: Cyclooxygenase (COX) is an intracellular enzyme that converts arachidonic acid to prostaglandin endoperoxide (PGG(2)). There are two isoforms of COX, namely constitutive COX-1 and inducible COX-2. It has been reported that COX-2 plays an important role in ischemia-reperfusion injury and that COX-2 mRNA and protein expression were up-regulated during cardiac allograft rejection. FK3311 is a suppressor of COX-2 activation. The purpose of this study was to evaluate the effectiveness of inhibiting COX-2 with FK3311 for the minimization of ischemia-reperfusion injury and for the improvement of donor heart function following transplantation in a canine model. MATERIALS AND METHODS: Adult mongrel dogs were used. After the measurement of hemodynamic parameters [cardiac output (CO), left ventricular pressure (LVP), and the maximum rates of increase and decrease in LVP (+/-LVdp/dt)], coronary vascular beds were washed out with a hypothermic (4 degrees C) University of Wisconsin (UW) solution following cardiac arrest in response to cold (4 degrees C) glucose-insulin-potassium solution. The heart was then excised and preserved in hypothermic (4 degrees C) UW solution for 12 h. FK3311 (3 mg/kg) was administered intravenously to five dogs prior to reperfusion, while vehicle was administered intravenously to a control group (n = 5). After 3 h of orthotopic transplantation using cardiopulmonary bypass, the hemodynamic parameters were compared with preoperative values of the donor animals under the condition of 10 mm Hg right atrial pressure and 5 mug/kg/min dopamine support. RESULTS: The recovery rates of CO and +/-LVdP/dt were significantly (P < 0.05) higher in the FK-treated dogs than in the controls (CO: 93 +/- 6 versus 66% +/- 4%; +LVdp/dt: 125 +/- 8 versus 77 +/- 10%; and -LVdp/dt: 81 +/- 7 versus 52 +/- 6%; for FK-treated versus control dogs, respectively). The recovery rate of LVP was higher in the FK-treated dogs than in the controls (90 +/- 5 versus 72 +/- 5%), but this difference was not statistically significant. Immunohistochemical staining revealed that COX-2 expression was reduced significantly in the myocardium of FK-treated dogs compared with controls. CONCLUSION: Hemodynamic parameters following transplantation were improved significantly in dogs treated with FK3311. Therefore, the inhibition of COX-2 improves transplanted cardiac function following long-term preservation.

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