Inhibition of cyclooxygenase-2 improves cardiac function following long-term preservation.
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.


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.


CONCLUSIONS
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.
Oshima
Kiyohiro
K
Department of Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
Takeyoshi
Izumi
I
Tsutsumi
Hirofumi
H
Mohara
Jun
J
Ohki
Shigeru
S
Koike
Norimasa
N
Nameki
Taro
T
Matsumoto
Koshi
K
Morishita
Yasuo
Y
D000241:Adenosine; D000493:Allopurinol; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004285:Dogs; D005978:Glutathione; D006334:Heart Function Tests / Q000187:drug effects; D016027:Heart Transplantation / Q000009:adverse effects*; D007328:Insulin; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009926:Organ Preservation; D019188:Organ Preservation Solutions; D011887:Raffinose; D016277:Ventricular Function, Left / Q000187:drug effects
D000813:Anilides; D052246:Cyclooxygenase 2 Inhibitors; D007328:Insulin; D019188:Organ Preservation Solutions; C055206:University of Wisconsin-lactobionate solution; C085566:FK 3311; D000493:Allopurinol; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose