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.