Beneficial effects of quinaprilat on coronary vasomotor function, endothelial oxidative stress, and endothelin activation after human heart transplantation

Background. We evaluated the potential of angiotensin-converting enzyme inhibition (ACEI) to modulate resting coronary vasomotor tone and endothelial dysfunction, and to decrease vascular oxidative stress and endothelin (ET)-1 activity in human heart transplant recipients. Methods. Coronary vasomotor responses and transcardiac metabolism of glutathione, oxidized glutathione, and ET-1 were determined before and after quinaprilat infusion in 32 heart transplant recipients. Furthermore, the potential effects of ACEI on endothelial oxidative stress, ET-1 activity, and nitrosoglutathione formation were investigated using endothelial cell cultures. Results. Epicardial diameter increased in response to quinaprilat by 6% +/- 1% (proximal segments; P < 0.05) and 14% +/- 3% (distal segments; P < 0.01). Coronary flow velocity increased by 2.2 +/- 0.2 (P<0.03). Coronary vasodilation to quinaprilat was negatively correlated with preexisting functional and structural coronary alterations. Quinaprilat selectively improved epicardial vasomotor response in segments with endothelial dysfunction, whereas microvascular endothelial dysfunction was unchanged. Transcardiac glutathione and big ET levels decreased after quinaprilat, whereas oxidized glutathione and ET-1 concentrations remained unchanged. Cell culture studies showed antioxidative effects of quinaprilat, revealed concentration-dependent down-regulation of endothelial ET-1 release, and indicated formation of nitrosoglutathione by quinaprilat. Conclusion. ACE regulates resting coronary vasomotor tone. Quinaprilat reduces vascular oxidative stress and ET-1 activity and mediates formation of nitrosoglutathione, effects that might contribute to long-term vasculoprotective effects of ACEI after heart transplantation.