[The protective effects and its underlying mechanism of 2,4-diamino-6-hydroxy-pyrimidine on postburn Staphylococcus aureus sepsis in rats].
OBJECTIVE
To investigate the protective effect and its underlying mechanism of 2,4-diamino-6-hydroxy-pyrimidine (DAHP), an inhibitor of GTP-cyclohydrolase I (GTP-CHI), on postburn Staphylococcus aureus (S. aureus) sepsis in rats.


METHODS
Fifty-six Wistar rats were randomly divided into four groups, i.e. normal control, scalding control, postburn sepsis group and DAHP treatment group. Tissue samples from liver, kidneys, lungs and heart were aseptically taken, and in which the GTP-CHI and inducible nitric oxide synthase (iNOS) contents and the mRNA expression of tumor necrosis factor-alpha (TNFalpha) were determined. Furthermore, biopterin (BH(4)) and nitric oxide (NO) levels in these tissue were also measured.


RESULTS
After the scalding injury followed by bacterial challenge, the GTP-CHI gene expression and biopterin levels were significantly increased in all tissue sampled, and so were iNOS mRNA expression and NO (P < 0.01), especially in liver and lungs. The expressions of GTP-CHI mRNA and iNOS mRNA and the production of BH(4) and NO in all tissue were evidently inhibited by the pretreatment with DAHP (P < 0.05 approximately 0.01). At the same time, the TNFalpha expression was also obviously decreased. In addition, The mortality at 6 hr in rats of DAHP treatment group was decreased.


CONCLUSIONS
The prognosis of the scalding rats complicated by sepsis caused by G(+) bacteria could be improved by DAHP pretreatment, which might be related to the inhibition of the production of BH(4) and NO by DAHP.
Yao
Yongming
Y
Burn Institute, The 304th Hospital of PLA, Beijing 100037, P.R. China.
Li
Hongyun
H
Dong
Ning
N
Yu
Yan
Y
Lu
Lianrong
L
Shi
Zhiguo
Z
Sheng
Zhiyong
Z
D000818:Animals; D001708:Biopterins / Q000378:metabolism; D002056:Burns / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006136:GTP Cyclohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D007042:Hypoxanthines / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000209:etiology / Q000517:prevention & control; D013203:Staphylococcal Infections / Q000209:etiology / Q000517:prevention & control*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D013400:Sugar Acids; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
C017182:5-dehydro-3-deoxy-D-arabino-heptulosonic acid-7-phosphate; D004791:Enzyme Inhibitors; D007042:Hypoxanthines; D012333:RNA, Messenger; D013400:Sugar Acids; D014409:Tumor Necrosis Factor-alpha; D001708:Biopterins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006136:GTP Cyclohydrolase; C017202:2,4-diaminohypoxanthine