This study investigated the protective effect of two nitric oxide synthase inhibitors N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 mg/kg i.p.) and aminoguanidine (AG, 400 mg/kg i.p.), and an antioxidant acetyl-L-carnitine (ALC, 250 mg/kg i.p., once daily for five days) against radiation-induced damage in Wistar rats. Blood samples were collected 6 h after whole-body irradiation with 8 Gy. Plasma concentrations of nitrite+nitrate (NO(x)) and malondialdehyde (MDA) were measured by high-performance liquid chromatography. A single injection of L-NAME one hour before exposure effectively prevented the radiation-induced elevation of plasma NO(x) and it reduced 2.6-fold the risk for death during the subsequent 30-day period. Pretreatment with ALC prevented the radiation-induced increase in plasma MDA and it had similar effect on mortality as L-NAME did. Presumably due to its short half-life, the partially iNOS-selective inhibitor and antioxidant AG given in a single dose before exposure did not attenuate MDA and NO(x) and it failed to significantly improve the 30-day survival. In conclusion, pretreatment with both the nonspecific NOS inhibitor L-NAME and the antioxidant ALC markedly reduce mortality to radiation sickness in rats. The radioprotective effect may be directly related to effective attenuation of the radiation-induced elevation of NO production by L-NAME and of oxidative stress by ALC.
- MeSH
- acylkarnitin terapeutické užití MeSH
- antioxidancia terapeutické užití MeSH
- guanidiny terapeutické užití MeSH
- krysa rodu rattus MeSH
- míra přežití MeSH
- NG-nitroargininmethylester terapeutické užití MeSH
- potkani Wistar MeSH
- radiační poranění patofyziologie prevence a kontrola MeSH
- radioprotektivní látky terapeutické užití MeSH
- synthasa oxidu dusnatého antagonisté a inhibitory MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
Purpose: The purpose of our study is to examine the effect of acetyl-L-carnitine (ALC) pretreatment on radiation pneumonitis and L-arginine-nitric oxide (NO) metabolic pathway after local chest irradiation. Materials and methods: Female Wistar rats were pretreated with either phosphate buffer saline or ALC and locally irradiated by a dose of 15 Gy onto the chest. Samples were collected 7 weeks after irradiation. Exhaled NO was monitored using chemiluminiscence method. In plasma and bronchoalveolar lavage (BAL) fluid, nitrite/nitrate (NOx) and malondialdehyde were measured by high-performance liquid chromatography. Total protein concentration was assayed colorimetrically. In lungs, inducible and endothelial nitric oxide synthase (iNOS, eNOS), arginase (Arg) I and II, cationic amino acid transporter (CAT) 1, 2 and 3 relative mRNA expression were measured by RT-PCR. Expression of Arg I and II was also evaluated by Western blot. Histochemical analysis was used to measure air/tissue ratio and neutrophil infiltration. Results:ALC pretreatment increased survival rate of irradiated rats. It also decreased NOx concentration in BAL, while in lungs, we observed increased air/tissue ratio, reduced neutrophil infiltration, decreased CAT 1 and CAT 3 mRNA expression, and reduced Arg I and Arg II expression. Conclusions:ALC pretreatment improves clinical prognosis and seems to reduce intensity of post-radiation changes on a molecular and microscopic level.
- MeSH
- acylkarnitin * aplikace a dávkování farmakologie MeSH
- arginin * metabolismus účinky záření MeSH
- bronchoalveolární lavážní tekutina chemie MeSH
- dechové testy metody MeSH
- hrudník účinky záření MeSH
- modely nemocí na zvířatech MeSH
- oxid dusnatý metabolismus účinky záření MeSH
- plíce * účinky záření MeSH
- potkani Wistar MeSH
- radiační pneumonitida farmakoterapie MeSH
- radioprotektivní látky * aplikace a dávkování MeSH
- Check Tag
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
PURPOSE: Nitric oxide (NO), a reactive radical, is formed in higher amounts from L-arginine by inducible NO synthase (iNOS) during early response to ionizing radiation presumably as a part of signal transduction pathways. This study investigated the changes in L-arginine-NO metabolic pathways within a 24-hour period after whole-body gamma irradiation of rats with the range of low to supra-lethal doses. MATERIALS AND METHODS: Young adult female Wistar rats received either 0-50 Gy whole-body irradiation or an intraperitoneal injection of bacterial lipopolysaccharide (LPS, 10 mg/kg). Exhaled NO was monitored using chemiluminiscence, nitrite + nitrate (NO(x)) and L-arginine were assayed by high-performance liquid chromatography, and expression of iNOS was determined using Western blot. RESULTS: Irradiation resulted in a dose-dependent increase of plasma NO(x) to maximum levels which were 4-fold higher compared to controls (p < 0.001). The NO(x) levels increased less in the bronchoalveolar lavage fluid (BAL) (1.7-fold, p < 0.001) and liver homogenate (2.5-fold, p < 0.05), respectively, and were dose-independent. Exhaled NO, lung NO(x), plasma and BAL L-arginine, and the expression of iNOS in lung and liver tissues of irradiated rats and controls were similar. LPS caused a considerable increase (p < 0.001) in exhaled NO (61-fold), NO(x) levels (plasma 34-fold, BAL 6-fold, lung 5-fold, liver 4-fold), and in iNOS expression, respectively. CONCLUSION: In contrast to the LPS treatment of rats, the radiation-induced changes in L-arginine-NO metabolic pathways are modest, particularly in the airways and lungs. Noninvasive measurement of exhaled NO within a 24-h period following the exposure of rats to ionizing radiation has no value for biodosimetry.
- MeSH
- arginin metabolismus účinky záření MeSH
- časové faktory MeSH
- celotělové ozáření MeSH
- enzymová indukce účinky záření MeSH
- krysa rodu rattus MeSH
- metabolické sítě a dráhy MeSH
- oxid dusnatý metabolismus účinky záření MeSH
- potkani Wistar MeSH
- synthasa oxidu dusnatého, typ II metabolismus účinky záření MeSH
- vztah dávky záření a odpovědi MeSH
- záření gama MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
