Effect of a neutrophil elastase inhibitor (ONO-5046 Na) on ischemia/reperfusion injury using the left-sided heterotopic canine heart transplantation model.
BACKGROUND
Ischemia/reperfusion injury is a major cause of transplanted heart dysfunction. Several reports have demonstrated that polymorphonuclear neutrophil (PMN) elastase derived from the activated neutrophils might play an important role in this injury. Herein, we investigated the protective effects of PMN elastase inhibitor (ONO-5046 Na) on ischemia/reperfusion injury using a left-sided canine heterotopic heart transplantation model.


METHODS
We used 10 pairs of adult beagle dogs. The donor heart was transplanted heterotopically into the left thoracic cavity of the recipient without cardiopulmonary bypass. A bolus of ONO-5046 Na (10 mg/kg) was introduced intravenously to 5 recipients (group II) at 15 minutes before reperfusion and was followed by continuous infusion (10 mg/kg per hour) for 180 minutes. Five dogs (group I) did not receive ONO-5046 Na and thus served as a control. After reperfusion, we evaluated transplanted heart function and obtained blood samples from the coronary sinus over a 360-minute period.


RESULTS
E(max) and pre-load recruitable stroke work in group II showed significantly better recovery than group I. Blood levels of PMN elastase, creatine kinase MB, lactate and inflammatory cytokines (tumor necrosis factor-alpha, interleukin-6, interleukin-8) were significantly lower in group II. Depletion of myocardial concentration of adenosine triphosphate at 120 minutes after reperfusion and myocardial water content was significantly lower in group II.


CONCLUSIONS
ONO-5046 Na, which inhibits PMN elastase, could reduce ischemia/reperfusion injury in heart transplantation. These results indicate that clinical application of ONO-5046 Na should be considered.
Ueno
M
M
Second Department of Surgery, Faculty of Medicine, Kagoshima University, Kagoshima, Japan. masahiro@med6.kufm.kagoshima-u.ac.jp
Moriyama
Y
Y
Toda
R
R
Yotsumoto
G
G
Yamamoto
H
H
Fukumoto
Y
Y
Sakasegawa
K
K
Nakamura
K
K
Sakata
R
R
D000818:Animals; D016207:Cytokines / Q000097:blood; D004285:Dogs; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology*; D016027:Heart Transplantation / Q000276:immunology*; D018836:Inflammation Mediators / Q000097:blood; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology; D015427:Reperfusion Injury / Q000276:immunology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013318:Stroke Volume / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D016042:Transplantation, Heterotopic / Q000276:immunology*
D016207:Cytokines; D018836:Inflammation Mediators; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; C069195:sivelestat; D019272:Leukocyte Elastase; D005998:Glycine