Role of Nitric Oxide and Reactive Oxygen Species in Cyclosporin-Induced Hypertension in Transplanted Patients.

Abstract

637 Hypertension is a major side effect of Cyclosporin (CsA). While mechanism/s responsible are unclear, CsA-induced endothelial dysfunction and CsA-induced hypertension has been attributed to CsA effect on the endothelial-derived factors controlling vasomotor tone. Endothelial NO is crucial in the manteinance of a state of basal vasodilation and recently an NO mediated counterregulatory mechanism protective from CsA-induced vasoconstriction has been suggested. Our study evaluates ecNOS gene status (Polymerase Chain Reaction analysis) and plasma level of NO metabolites (NO2−/NO3−) (ELISA) in 10 heart (HT) and 10 kidney (KT) transplanted patients under chronic CsA treatment with CsA-induced hypertension. Diagnosis of CsA-induced hypertension in HT was based on the development of hypertension only after CsA administration and without improvement after the tapering of steroids associated to CsA. In KT, by the development of hypertension only after transplant, for those normotensive before the transplant, and by the worsening of a preexisting hypertension notwithstanding the tapering of steroids associated to CsA treatment. Since CsA increases superoxide anions, which combine with NO to yield peroxynitrite, a powerful oxidant, plasma peroxynitrites and hydroperoxides were evaluated (HPLC) as index of the presence of superoxides and free radicals and therefore of oxidative stress. 10 healthy subjects were used as controls (C). Quantification of monocyte ecNOS mRNA from patients and controls demonstrated NO system up regulation in patients notwithstanding the hypertension. The mean ecNOS to β-actin ratio was 1.80±0.85 in patients vs 0.40±0.09 in C (p<0.04). (NO2−/NO3−) plasma level was 34.03±14.32 mM in patients vs 11.53±5.64, p<0.001. Hydroperoxides were also increased in patients vs C: 3.4±1.4 i.a.u. vs 1.3±0.6, p<0.007 (from colesterol esters) and 10.6±6.4 vs 1.3±0.8, p<0.008 (from triglycerides) as well as peroxynitrite plasma level (0.32±0.11 mM/L vs undetectable in C. This study confirms a CsA induced NO system up regulation in transplanted patients. However, the counterregolatory system to CsA-induced vasoconstriction could be canceled in patients by CsA induced superoxides and free radicals production which, increasing NO metabolism and therefore reducing its efficacy as vasorelaxing factor could contribute to CsA induced vasoconstriction and hypertension and promoting remodelling processes, predispose to long term hypertensive complications such as cardiac hypertrophy and atherosclerosis.