Background: CsA-induced endothelial dysfunction and CsA-induced hypertension have been attributed to CsA effects on the endothelial-derived factors controlling vasomotor tone, but the mechanisms responsible are unclear. Endothelial nitric oxide (NO) is known to maintain a state of basal vasodilation and recently a NO mediated counterregulatory mechanism protective from CsA-induced vasoconstriction has been suggested.
Patients and methods: Our study evaluates ecNOS gene status and NO metabolites in kidney transplanted patients under chronic CsA treatment with CsA-induced hypertension. Since CsA increases superoxide production, which metabolizes NO, plasma hydroperoxides and peroxynitrite were also evaluated as index of the presence of "oxidative stress".
Results: Quantification of monocyte ecNOS mRNA and NO metabolites plasma level from patients and control subjects (C) demonstrated NO system up regulation in patients notwithstanding hypertension. The mean ecNOS to beta-actin ratio was 2.00 +/- 0.87 vs 0.29 +/- 0.08 in C, p < 0.04. NO metabolite plasma level was 30.03 +/- 9.62 mM vs 9.37 +/- 3.86, p < 0.001. Hydroperoxides were also increased in patients: 3.6 +/- 1.6 i.a.u. vs 1.4 +/- 0.8, p < 0.007 (from cholesterol esters) and 10.8 +/- 6.6 vs 1.5 +/- 0.9, p < 0.008 (from triglycerides) as well as peroxynitrite plasma level: 0.36+/- 0.14 mM/L vs undetectable in C.
Conclusions: This study confirms a NO system up-regulation in transplanted patients. However, the counterregolatory system to CsA-induced vasoconstriction, could be cancelled by CsA induced superoxide and free radicals production which, increasing NO metabolism could contribute to CsA induced vasoconstriction and hypertension.