title: Cyclosporin-induced endothelial dysfunction and hypertension: are nitric oxide system abnormality and oxidative stress involved?
abstract: Hypertension is a major side effect of cyclosporin (CsA). While the mechanism(s) responsible are unclear, CsA-induced endothelial dysfunction and CsA-induced hypertension have been attributed to the CsA effect on the endothelial-derived factors controlling vasomotor tone. Endothelial nitric oxide (NO) is crucial in the maintenance of a state of basal vasodilation, and recent studies have suggested an NO-mediated counterregulatory mechanism protective from CsA-induced vasoconstriction. Our study evaluates endothelial nitric oxide synthase (ecNOS) gene status (PCR analysis) and plasma levels of NO metabolites (ELISA) in kidney and heart transplant patients under chronic CsA treatment with CsA-induced hypertension. Since CsA increases superoxide production, which metabolises NO, plasma hydroperoxides from cholesterol esters and from triglycerides and peroxynitrite were also evaluated (HPLC) as an index of the presence of superoxides and of "oxidative stress". Quantification of monocyte ecNOS mRNA and NO metabolites plasma levels from patients and controls (C) demonstrated NO system upregulation in patients notwithstanding the hypertension. The mean ecNOS to beta-actin ratio was 1.80 +/- 0.85 in patients vs 0.40 +/- 0.09 in C (P < 0.04). NO metabolites were 34.03 +/- 14.32 microM in patients vs 11.53 +/- 5.64 microM in C (P < 0.001). Hydroperoxides from cholesterol esters and from triglycerides were also increased in patients, 3.4 +/- 1.4 vs 1.3 +/- 0.6 integrated area units (i. a. u.), P < 0.007 and 10.6 +/- 6.4 vs 1.3 +/- 0.8 i. a. u., P < 0.008, respectively, as well as the peroxynitrite plasma level, 0.32 +/- 0.11 microM/l vs undetectable in C. This study confirms a CsA-induced NO system upregulation in transplanted patients. However, the NO-mediated counterregulatory system to CsA-induced vasoconstriction, present in normals, could be canceled in patients by CsA-induced superoxide (O2-) and free radical production which, by increasing NO metabolism, could contribute to CsA-induced vasoconstriction and hypertension and predispose to atherosclerosis.
authors: Department of Medical and Surgical Sciences, University of Padua, Italy. renzcalo@ux1.unipd.it
authors: L
authors: L
authors: Calò
authors: A
authors: A
authors: Semplicini
authors: P A
authors: PA
authors: Davis
authors: P
authors: P
authors: Bonvicini
authors: S
authors: S
authors: Cantaro
authors: P
authors: P
authors: Rigotti
authors: A
authors: A
authors: D'Angelo
authors: U
authors: U
authors: Livi
authors: A
authors: A
authors: Antonello
mesh_terms: D000328:Adult; D016572:Cyclosporine / Q000009:adverse effects*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000209:etiology*; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D016030:Kidney Transplantation / Q000276:immunology* / Q000502:physiology; D008054:Lipid Peroxides / Q000097:blood; D008297:Male; D008875:Middle Aged; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III; D009589:Nitrogen Oxides / Q000097:blood; D016877:Oxidants / Q000097:blood; D018384:Oxidative Stress / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D007166:Immunosuppressive Agents; D008054:Lipid Peroxides; D009566:Nitrates; D009589:Nitrogen Oxides; D016877:Oxidants; C039642:peroxynitric acid; D009569:Nitric Oxide; D016572:Cyclosporine; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III