2-4-diaminohypoxanthine and Burns

Guanosine triphosphate-cyclohydrolase I (GTP-CHI) is the first and rate-limiting enzyme for the de novo biosynthesis of biopterin. The objective of present study was to observe the effect of 2,4-diamino-6-hydroxy-pyrimidine (DAHP), an inhibitor of GTP-CHI, on the development of postburn Staphylococcus aureus sepsis.. A prospective, controlled animal study.. A research laboratory in a hospital.. Male Wistar rats.. Fifty-six male Wistar rats were randomly divided into four groups as follows: normal control group (n = 10), scald control group (n = 10), postburn sepsis group (n = 20), and DAHP treatment group (n = 16). In the scald control group, rats were subjected to a 20% total body surface area third-degree scald injury and then were killed at 24 hrs. In the postburn sepsis group (n = 20), rats were inflicted with 20% total body surface area third-degree scald followed by Staphylococcus aureus challenge, and they were further divided into 2- and 6-hr groups. In the DAHP treatment group (n = 16), animals were intraperitoneally injected with a dose of 1 g/kg DAHP before Staphylococcus aureus challenge and then were further divided into 2- and 6-hr groups. Tissue samples from liver, kidneys, lungs, and heart were collected to determine GTP-CHI, inducible nitric oxide synthase, and tumor necrosis factor-alpha messenger RNA expression. Meanwhile, biopterin and nitric oxide concentrations in these tissues were also measured.. After the scald injury followed by Staphylococcus aureus challenge, GTP-CHI messenger RNA expression and biopterin concentrations were significantly elevated in various tissues such as liver, heart, kidneys, and lungs, as were the values of inducible nitric oxide synthase messenger RNA expression and nitric oxide formation (p <.01). Pretreatment with DAHP significantly reduced GTP-CHI/biopterin induction (p <.05-.01), and the up-regulation of inducible nitric oxide synthase/nitric oxide was also suppressed. Furthermore, DAHP administration inhibited the gene expression of tumor necrosis factor-alpha. Two hours after septic challenge, tumor necrosis factor-alpha messenger RNA expression in liver, kidneys, and lungs in the DAHP-treated group was 35.7%, 37.3%, and 33.0% of that in the postburn septic group, respectively. Additionally, in animals without DAHP treatment, the 6-hr mortality rate was 55.6% (20 of 36), whereas it was only 25.0% in DAHP-treated animals (4 of 16, p =.08).. Early treatment with DAHP might be a potential strategy to prevent the development of postburn Staphylococcal sepsis, which appears to be associated with down-regulation of biopterin and nitric oxide formation by DAHP.

Topics: Analysis of Variance; Animals; Biopterins; Burns; Down-Regulation; Enzyme Inhibitors; GTP Cyclohydrolase; Hypoxanthines; Male; Nitric Oxide; Nitric Oxide Synthase; Prospective Studies; Random Allocation; Rats; Rats, Wistar; RNA, Messenger; Sepsis; Staphylococcal Infections

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.. 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.. 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.. 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.

Topics: Animals; Biopterins; Burns; Enzyme Inhibitors; Gene Expression Regulation; GTP Cyclohydrolase; Heart; Hypoxanthines; Kidney; Liver; Lung; Male; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar; RNA, Messenger; Sepsis; Staphylococcal Infections; Staphylococcus aureus; Sugar Acids; Time Factors; Tumor Necrosis Factor-alpha