Coronary artery endothelial dysfunction after ischemia-reperfusion and acute untreated rejection in a canine heterotopic heart transplantation model.
BACKGROUND
Acute rejection is a common problem in heart transplantation and may contribute to the development of cardiac allograft vasculopathy. This study was designed to evaluate the mechanisms of coronary endothelial dysfunction associated with ischemia-reperfusion and acute untreated rejection.


METHODS
Two groups of mongrel dogs (n=7 per group) underwent heterotopic cervical heart transplantation without immunosuppression. Allografts were harvested on posttransplant day 1 (group 1) and day 5 (group 2). A third group of unoperated dogs served as control (group 3). After harvesting, epicardial coronary arteries were studied in organ chamber for endothelium-dependent and independent reactivity.


RESULTS
Group 1 displayed multifocal ischemic damage without any rejection while hearts from group 2 reached grade IV rejection. Immunohistochemical studies for von Willebrand factor showed expression on coronary endothelial cells in all animals with scattered areas of denudation in transplanted groups. Endothelium-dependent responses to acetylcholine, calcium ionophore A23147, and bradykinin were unaffected in groups 1 and 2. Endothelial relaxations to sodium fluoride (Gi-protein activator) was significantly reduced in group 1 and significantly increased in group 2 compared with control. Responses to serotonin and UK14304 (receptors linked to Gi-protein) were significantly increased in group 2. Responses to thrombin were decreased in both groups. Endothelium-independent responses were unaffected.


CONCLUSIONS
In the canine model of heterotopic heart transplantation, the early (24 hr) endothelial dysfunction seen after transplantation is specific to the thrombin receptor and the Gi-protein signaling pathway. Acute untreated rejection did not modify the alteration in endothelial reactivity to thrombin but enhanced the sensibility of the Gi-protein signaling pathways.
Demers
P
P
Department of Surgery and the Research Center, Montreal Heart Institute,  Quebec, Canada.
Elkouri
S
S
Sirois
M G
MG
Cartier
R
R
D000818:Animals; D003327:Coronary Disease / Q000150:complications / Q000503:physiopathology*; D004285:Dogs; D004730:Endothelium, Vascular / Q000201:enzymology; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology; D006084:Graft Rejection / Q000209:etiology* / Q000628:therapy; D016027:Heart Transplantation / Q000276:immunology / Q000502:physiology; D007150:Immunohistochemistry; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D015427:Reperfusion Injury / Q000209:etiology*; D015398:Signal Transduction; D016042:Transplantation, Heterotopic
D011189:Potassium Chloride; D019001:Nitric Oxide Synthase; D019204:GTP-Binding Proteins