FK409 ameliorates ischemia-reperfusion injury in heart transplantation following 12-hour cold preservation.
OBJECTIVE
FK409 is the first spontaneous nitric oxide donor to increase plasma guanosine 3':5'-cyclic monophosphate. We designed this study to investigate whether the administration of FK409 during reperfusion ameliorated ischemia-reperfusion injury and enhanced post-transplant graft function in orthotopic heart transplantation following 12-hour cold preservation in a canine model.


METHODS
We used 10 pairs of adult mongrel dogs, weighing 9.5 to 13.5 kg. Following cardiac arrest using cardioplegia, we washed out the coronary vascular beds with cold University of Wisconsin solution followed by 12-hour preservation. After preservation, we performed orthotopic transplantation. The experimental animals were divided into 2 groups. In the FK group (n = 5), FK409 (5 microg/kg/min) was administered intravenously, beginning 15 minutes before the onset of reperfusion and continuing for 45 minutes after reperfusion. In the control group (n = 5), saline vehicle was administered in the same manner. Two hours after transplantation, we assessed cardiac function, including cardiac output, left ventricular systolic pressure (LVP), and the maximum rates of positive and negative increase of LVP (+/-LV dP/dt) by comparing the recovery rate (%) of the cardiac function of the donor animal. We measured endothelin-1 levels in blood obtained from a catheter inserted into the coronary sinus 30, 60, and 120 minutes after reperfusion.


RESULTS
Cardiac output was higher in the FK group than in the control group, but the difference was not significant (p = 0.08). Left ventricular systolic pressure and +/-LV dP/dt were significantly (p < 0.05) higher in the FK group than in the control group. Endothelin-1 levels were significantly (p < 0.05) lower in the FK group than in the control group 30 minutes after reperfusion. Transmission electron microscopy showed that the basal lamina of capillary vessels, glycogen granules, and mitochondrial structure were well-preserved in the FK group.


CONCLUSIONS
In orthotopic transplantation models, FK409 is effective in ameliorating ischemia-reperfusion injury following preservation and in enhancing post-transplant cardiac function.
Mohara
J
J
Second Department of Surgery, Gunma University School of Medicine, Maebashi, Gunma, Japan.
Oshima
K
K
Tsutsumi
H
H
Takeyoshi
I
I
Matsumoto
K
K
Morishita
Y
Y
D000241:Adenosine / Q000494:pharmacology; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D003080:Cold Temperature / Q000009:adverse effects; D004285:Dogs; D019332:Endothelin-1 / Q000097:blood; D005978:Glutathione / Q000494:pharmacology; D016027:Heart Transplantation; D007262:Infusions, Intravenous; D007328:Insulin / Q000494:pharmacology; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D020030:Nitric Oxide Donors / Q000008:administration & dosage*; D009574:Nitro Compounds / Q000008:administration & dosage*; D009926:Organ Preservation / Q000009:adverse effects*; D019188:Organ Preservation Solutions / Q000494:pharmacology; D011887:Raffinose / Q000494:pharmacology; D020127:Recovery of Function / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D017725:Ventricular Pressure / Q000187:drug effects
D019332:Endothelin-1; D007328:Insulin; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D019188:Organ Preservation Solutions; C055206:University of Wisconsin-lactobionate solution; D000493:Allopurinol; C061872:FK 409; D000254:Sodium-Potassium-Exchanging ATPase; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose