Nifedipine prevents changes in nitric oxide synthase mRNA levels induced by cyclosporine.
Cyclosporine toxicity mainly affects kidney and liver function. We have previously shown that cyclosporine nephrotoxicity alters kidney nitric oxide synthase mRNA pattern of expression. To determine if nitric oxide synthase expression changes are mediated directly by cyclosporine or by secondary hemodynamic alterations induced by cyclosporine, we evaluated if these effects are tissue specific and if nifedipine-induced vasodilation prevents these alterations. Uninephrectomized Wistar rats treated for 7 days with olive oil, cyclosporine (30 mg/kg), nifedipine (3 mg/kg), and nifedipine+cyclosporine were studied. In vehicle and cyclosporine groups, the gene expression of the neuronal, inducible, and endothelial nitric oxide synthases in cerebellum, heart, intestine, liver, renal cortex, and medulla was evaluated. The administration of cyclosporine was associated with nephrotoxicity and hepatotoxicity, increased endothelial nitric oxide synthase mRNA levels in renal cortex and liver, and a decrease in inducible nitric oxide synthase and neuronal nitric oxide synthase in renal medulla. The mRNA levels of the 3 nitric oxide synthase isoforms were not affected in any other tissue. Nifedipine did not alter nitric oxide synthase expression in the control group but prevented changes associated with cyclosporine. These results suggest that cyclosporine-induced changes in the pattern of expression of the nitric oxide synthases may be secondary to its hemodynamic effects.
Sánchez-Lozada
L G
LG
Department of Nephrology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico.
Gamba
G
G
Bolio
A
A
Jiménez
F
F
Herrera-Acosta
J
J
Bobadilla
N A
NA
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology* / Q000633:toxicity; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007672:Kidney Cortex / Q000187:drug effects / Q000201:enzymology; D007679:Kidney Medulla / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008111:Liver Function Tests; D008297:Male; D009392:Nephrectomy; D009543:Nifedipine / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009928:Organ Specificity; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D007527:Isoenzymes; D012333:RNA, Messenger; D016572:Cyclosporine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496322:Nos1 protein, rat; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D009543:Nifedipine