Nicorandil, a potent adenosine triphosphate-sensitive potassium-channel opener, ameliorates lung allograft reperfusion injury.
BACKGROUND
Lung allograft ischemia-reperfusion injury, characterized by increased pulmonary vascular resistance, pulmonary edema, and hypoxia, is the most frequent cause of early graft failure. Exogenous nitric oxide has been shown to reduce lung allograft reperfusion injury. During hypoxia, the adenosine triphosphate-sensitive potassium channel is an important ionic channel that links the bioenergetic metabolism to membrane excitability. It has been shown to play a critical role in vascular permeability and in activation of neutrophils and their subsequent interaction with vessel wall cellular components. The purpose of this study was to investigate whether nicorandil, a novel nitric oxide generator and adenosine triphosphate-sensitive potassium-channel opener, might enhance lung preservation and prevent allograft reperfusion injury.


METHODS
Fourteen dogs underwent left lung allotransplantation. Donor lungs were flushed with modified Euro-Collins solution and stored for 21 hours at 1 degree C. Immediately after transplantation, the contralateral right main pulmonary artery and bronchus were ligated to assess isolated allograft function. Hemodynamics and arterial blood gas analysis (inspired oxygen fraction 1.0) were assessed for 6 hours before the dogs were put to death. After the assessment, activity of allograft myeloperoxidase and protein levels of bronchoalveolar lavage fluid were measured. Control animals (group I, n = 5) received no nicorandil. In group II (n = 5), the donor lung received nicorandil (24 mg/L) in the flush solution. In addition, recipient animals received nicorandil (0.5 mg/kg, intravenously) just before reperfusion, as well as a continuous infusion (0.74 +/- 0.03 mg/kg per hour) during the 6-hour assessment period. In group III (n = 4), glibenclamide, a selective adenosine triphosphate-sensitive potassium-channel blocker, was administered 15 minutes before nicorandil administration to both donor and recipient. The animals in group III received nicorandil in the same regimen as group II.


RESULTS
Superior gas exchange and hemodynamics were observed in lungs receiving only nicorandil. Allograft myeloperoxidase activity and protein levels in bronchoalveolar lavage fluid were significantly reduced in group II. Glibenclamide eliminated the beneficial effects of nicorandil.


CONCLUSIONS
Nicorandil administration in the flush solution and during the reperfusion period ameliorates lung allograft dysfunction, improves blood flow, and reduces pulmonary vascular resistance and myeloperoxidase activity in the transplanted lung. The present study suggests that nicorandil reduces lung allograft reperfusion injury. The beneficial effects of nicorandil may be attributed to its properties as an adenosine triphosphate-sensitive potassium-channel opener.
Department of Surgery, Washington University School of Medicine, Barnes Hospital, St. Louis, Mo 63110, USA.
M
M
Yamashita
R A
RA
Schmid
S
S
Fujino
J D
JD
Cooper
G A
GA
Patterson
D000818:Animals; D004285:Dogs; D006439:Hemodynamics; D008168:Lung / Q000098:blood supply* / Q000187:drug effects; D016040:Lung Transplantation / Q000009:adverse effects / Q000502:physiology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D020108:Nicorandil; D015221:Potassium Channels / Q000187:drug effects*; D015427:Reperfusion Injury / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*; D014184:Transplantation, Homologous
D015221:Potassium Channels; D009536:Niacinamide; D020108:Nicorandil