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

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.

• Authors: Kiyohiro Oshima, Izumi Takeyoshi, Hirofumi Tsutsumi, Jun Mohara, Shigeru Ohki, Norimasa Koike, Taro Nameki, Koshi Matsumoto, Yasuo Morishita
• Journal: The Journal of surgical research (J Surg Res) Vol. 135 Issue 2 Pg. 380-4 (Oct 2006) ISSN: 0022-4804 [Print] United States
• PMID: 16713604 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Anilides
• Cyclooxygenase 2 Inhibitors
• Insulin
• Organ Preservation Solutions
• University of Wisconsin-lactobionate solution
• FK 3311
• Allopurinol
• Glutathione
• Adenosine
• Raffinose

Topics

• Adenosine
• Allopurinol
• Anilides (pharmacology)
• Animals
• Blood Pressure (drug effects)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Dogs
• Glutathione
• Heart Function Tests (drug effects)
• Heart Transplantation (adverse effects)
• Insulin
• Myocardial Reperfusion Injury (prevention & control)
• Organ Preservation
• Organ Preservation Solutions
• Raffinose
• Ventricular Function, Left (drug effects)