Depressed renal and vascular nitric oxide synthase expression in cyclosporine-induced hypertension.
BACKGROUND
Introduction of cyclosporine (CsA) for clinical use has greatly enhanced the outcome of organ transplantation. However, CsA can cause nephrotoxicity and hypertension (HTN). This study was designed to test the hypothesis that CsA-induced HTN is related to depressed nitric oxide (NO) production.


METHODS
Urinary excretion of NO metabolites (NOx) and endothelial and inducible NO synthase (eNOS and iNOS) proteins were determined in thoracic aortas and kidneys of CsA-treated (given CsA 18 mg/kg/day for 3 weeks) and placebo-treated rats. In addition, renal tissue eNOS and iNOS mRNA and aorta iNOS activity were measured.


RESULTS
CsA administration resulted ina significant rise in arterial blood pressure (BP) coupled with a steady decline in urinary NOx excretion, suggesting depressed NO production. This was accompanied by a significant reduction in iNOS protein abundance in the kidney and thoracic aorta but no change in eNOS protein abundance. The fall in renal iNOS protein in CsA-treated rats was accompanied by a parallel decline in iNOS mRNA abundance and enzymatic activity.


CONCLUSIONS
Administration of CsA for three weeks resulted in a significant rise in BP together with marked reductions in urinary NOx excretion, and renal and vascular iNOS expression. These observations suggest that CsA-induced HTN may be, in part, related to impaired NO production. If true, strategies designed to restore NO availability may mitigate HTN and other vascular complications of CsA therapy.
Vaziri
N D
ND
Department of Medicine, University of California, Irvine, USA. tabotten@uci.edu
Ni
Z
Z
Zhang
Y P
YP
Ruzics
E P
EP
Maleki
P
P
Ding
Y
Y
D000818:Animals; D001011:Aorta / Q000201:enzymology*; D016572:Cyclosporine / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced* / Q000201:enzymology; D007668:Kidney / Q000201:enzymology*; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019323:omega-N-Methylarginine / Q000494:pharmacology
D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D016572:Cyclosporine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat