Status of the endothelium-derived hyperpolarizing factor pathway in coronary arteries after heterotopic heart transplantation

Background: After the first year of transplantation, the major limitation to long-term survival is the development of graft coronary vasculopathy, characterized by a pathologic activation of the endothelium with an attendant loss of its regulatory properties on homeostasis of the vascular wall. The present study was designed to evaluate the integrity of coronary vascular relaxations attributed to the endothelium-derived hyperpolarizing factor (EDHF) and to study hyperpolarization of smooth muscle cells after heterotopic heart transplantation. Methods: Six weeks after heart transplantation in a porcine model, vascular reactivity studies of control, native and allograft epicardial coronary artery rings were performed in standard organ chamber experiments. Moreover, membrane potential measurements were made with intracellular microelectrodes in rings of native and allograft coronary arteries. Results: There was a significant decrease in endothelium-dependent relaxations to 5-hydroxytryptamine (5-HT), high doses of bradykinin (BK) alone and BK plus N-omega-nitro-L-arginine (L-NNA) in rings from allograft compared to native, whereas the variation was significantly increased in response to cromakalim, a K+-ATP channel opener. Electrical and mechanical recordings showed no alteration in the resting membrane potential of smooth muscle cells, depolarization during contraction to prostaglandin F-2 alpha (PGF(2 alpha)), or hyperpolarization in the presence of BK + L-NNA in rings of allograft vs native. Conclusions: In this swine model of heart transplantation, part of the reduction in endothelium-dependent relaxations to BK may be attributed to an alteration in the activity of EDHF. This impairment of EDHF-mediated relaxations may compound the endothelial dysfunction preceding the development of coronary graft vasculopathy.