Impairment of G-protein-mediated signal transduction in the porcine coronary endothelium during rejection after heart transplantation

Background: Endothelial dysfunction is an early event leading to atheroscle rosis. It also occurs after orthotopic heart transplantation and can be use d to predict the development of intimal hyperplasia in the coronary artery wall. The present study was designed to assess the time course and specific alterations underlying endothelial dysfunction due to rejection after hear t transplantation. Methods: A porcine model of heterotopic heart transplant ation was used. Preoperative serum typing for the class I antigen of the sw ine lymphocyte alloantigen was performed to ensure compatibility for this a ntigen. This permitted survival of the graft with a low grade rejection wit hout immunosuppression. Rings (with or without endothelium) of epicardial c oronary arteries of native and transplanted hearts were studied in organ ch ambers filled with modified Krebs-Ringer bicarbonate solution and compared 1, 30 and 60 days after transplantation. Results: Myocardial contractility was normal in all grafts studied at 60 days after transplantation and all c oronary arteries were patent. Myocardial biopsies showed the progression of rejection from day 1 to day 60 after implantation. All endothelium-depende nt relaxations were normal one day after transplantation. Endothelium-depen dent relaxations to serotonin and to the alpha(2)-adrenergic agonist UK1430 4 (which both activate receptors coupled to Gi-proteins) and to sodium fluo ride (a direct activator of G-proteins) were decreased 30 days after transp lantation, while those to the calcium ionophore, A23187, and bradykinin wer e shifted to the right and those to ADP were normal. At 60 days, endotheliu m-dependent relaxations mediated by the Gi-protein pathway were decreased f urther while the concentration-relaxation curves to the other agonists were further shifted to the right. Endothelium-independent relaxations to the n itric oxide donor, Sin-1, were progressively reduced at 30 and 60 days, but maximal relaxations were maintained at 60 days. Histomorphometric studies showed a progressive increase in the percentage of coronary rings with inti mal thickening from day 1 to day 60 after transplantation. Conclusions: The progressive endothelial dysfunction reported in this model of accelerated coronary atherosclerosis after transplantation without immunosuppression in volves preferentially the pertussis-toxin-sensitive Gi-protein-mediated pat hway. Endothelium-independent relaxations are decreased at 60 days, as are all other endothelium-dependent relaxations. Decreased endothelium-dependen t vasodilatation may contribute to the development of coronary graft vascul opathy. (C) 1999 Published by Elsevier Science B.V. All rights reserved.