title: Vascular changes in cyclosporine A-induced hypertension and nephrotoxicity in spontaneously hypertensive rats on high-sodium diet.
abstract: Functional and morphological changes of blood vessels in cyclosporine A (CsA)-induced hypertension and nephrotoxicity were studied in spontaneously hypertensive rats (SHR). The role of the L-arginine-nitric oxide (NO) pathway and the importance of oxidative stress in CsA toxicity were also assessed. SHR (7-8 week old) on a high-sodium diet were treated with CsA (5 mg kg(-1) d(-1) s.c.) for 6 weeks. A proportion of the rats were treated concomitantly with the NO precursor L-arginine (1.7 g kg(-1)d(-1) p.o.). CsA elevated blood pressure and caused renal dysfunction and morphological nephrotoxicity. CsA also impaired mesenteric and renal arterial function and caused structural damage to intrarenal and extrarenal small arteries and arterioles. Medial atrophy of the mesenteric resistance vessels and decreased viability of smooth muscle cells of the thoracic aorta were observed. Renal and arterial damage was associated with the presence of inflammatory cells. CsA did not affect markers of the L-arginine-NO pathway (urinary cyclic GMP excretion or endothelial or inducible NO synthase expression in kidney, aorta or heart) or oxidative stress (urinary excretion of 8-isoprostaglandin F2alpha, plasma urate concentration or total radical trapping capacity). Concomitant L-arginine treatment did not affect CsA-induced changes in blood pressure or histological findings but tended to alleviate the arterial dysfunction. The renal and cardiovascular toxicity of CsA was associated with arterial dysfunction and morphological changes in small arteries and arterioles in SHR on a high-sodium diet. The findings did not support the role of oxidative stress or a defect in the L-arginine-NO pathway.
authors.affiliation: Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Lassila
authors.forename: J
authors.initials: J
authors.lastname: Santisteban
authors.forename: P
authors.initials: P
authors.lastname: Finckenberg
authors.forename: P
authors.initials: P
authors.lastname: Salmenperä
authors.forename: A
authors.initials: A
authors.lastname: Riutta
authors.forename: E
authors.initials: E
authors.lastname: Moilanen
authors.forename: I
authors.initials: I
authors.lastname: Virtanen
authors.forename: H
authors.initials: H
authors.lastname: Vapaatalo
authors.forename: M L
authors.initials: ML
authors.lastname: Nurminen
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000378:metabolism / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D001808:Blood Vessels / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology* / Q000633:toxicity; D006321:Heart / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000633:toxicity; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D009929:Organ Size; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D012982:Sodium, Dietary / Q000008:administration & dosage*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D007166:Immunosuppressive Agents; D012982:Sodium, Dietary; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; D011189:Potassium Chloride; D016572:Cyclosporine; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D000109:Acetylcholine; D009638:Norepinephrine