Endothelium-dependent vasodilation during acute rejection in dogs

Background Acute rejection, which is a major cause of death after cardiac transplantation, is associated with increased coronary artery resistance and decreased coronary blood flow, leading to congestive heart failure. Materials and methods To examine the contribution of endothelium-derived vasoactive factors on coronary artery tone during acute rejection, dogs underwent orthotopic heart transplantation without immunosuppression. Plasma levels of endothelin, a potent endogenous vasoconstrictor peptide, and atrial natriuretic peptide, an endogenous coronary vasodilator of cardiac origin, were measured daily by radioimmunoassay until sacrifice. Results Over 7 days, all animals developed acute rejection accompanied by progressive increases in plasma endothelin (10 ± 3 to 25 ± 4 pg/ml, n = 6, P < 0.05) and atrial natriuretic peptide (57 ± 10 to 188 ± 42 pg/ml, n = 6, P < 0.05). However, in organ chamber experiments, coronary artery segments from rejecting hearts exhibited normal endothelium-dependent vasodilation to acetylcholine, adenosine diphosphate, and the calcium ionophore A23187. In addition, coronary arteries exhibited normal relaxation to sodium nitroprusside (cyclic guanosine monophosphate-dependent) and isoproterenol (cyclic adenosine monophosphate-dependent). Conclusions In early, untreated acute rejection after orthotopic heart transplantation, graft dysfunction is not associated with impaired endothelium-dependent coronary artery vasodilation but may result from enhanced production of endothelin, a potent vasoconstrictor.