A precursor of the nitric oxide donor SIN-1 modulates the stress protein heme oxygenase-1 in rat liver.
In this study the effect of increased nitric oxide (NO) production on the expression of rat liver heme oxygenase-1, an inducible stress protein responsible for the catalysis of heme to biliverdin and carbon monoxide, was investigated. Rats were injected intraperitoneally with molsidomine (SIN-10), a long acting drug that is enzymatically converted in the liver to yield the active NO-releasing agent 3-morpholinosydnonimine (SIN-1). Administration of SIN-10 resulted in a significant time- and dose-dependent increase in plasma levels of nitrite/nitrate, an index of NO release. A time course of heme oxygenase-1 mRNA levels in liver showed a gradual increase in the expression of the gene encoding for this protein, which was maximal at 4 hours and returned to normal levels by 6 hours after SIN-10 treatment. Heme oxygenase activity also increased by 50% at 4 hours and was maximal 12 hours after SIN-10 administration (63% increase over baseline). These results indicate a possible role for locally generated NO in the modulation of hepatic stress response in vivo suggesting that NO mediates cell adaptation to stress by activation of endogenous defensive mechanisms.
Motterlini
R
R
Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex, United Kingdom. r.motterlini@ic.ac.uk
Hidalgo
A
A
Sammut
I
I
Shah
K A
KA
Mohammed
S
S
Srai
K
K
Green
C J
CJ
D000818:Animals; D015152:Blotting, Northern; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D011355:Prodrugs / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D014158:Transcription, Genetic / Q000187:drug effects
D006360:Heat-Shock Proteins; D009566:Nitrates; D009573:Nitrites; D011355:Prodrugs; D012333:RNA, Messenger; C002385:linsidomine; D008981:Molsidomine; D006419:Heme Oxygenase (Decyclizing)