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.

We found a chronological and dose-dependent order of p38 activation and TGF-β1 expression in apical enterocytes. Transient up-regulation of p38 and TGF-β1 signalling observed 4 h after low-dose irradiation may participate in molecular mechanisms creating cellular over-expression in apical compartment, while persistent patterns measured 24 h after high-dose irradiation might provide protection of remaining cells in order to maintain tissue integrity.

1.  Rodent studies have documented that N(ω)-hydroxy-nor-L-arginine (nor-NOHA), an arginase inhibitor, has therapeutic potential in the treatment of cardiovascular and obstructive airway diseases. However, its bioavailability and pharmacokinetics have not been described so far. 2.  Anesthetized brown Norway rats were administered single doses of nor-NOHA (10, 30 or 90 mg/kg) intravenously (i.v.), intraperitonealy (i.p.) or via intratracheal (i.t.) instillation of aerosol. Plasma nor-NOHA was assayed using a validated HPLC method. 3.  Upon i.v. administration, the mean concentration showed a biphasic decline and its value dropped below 10% of the maximum after 20 min. The pharmacokinetics were linear with the total and inter-compartmental clearances of 33 and 17 mL/min/kg, central and peripheral volumes of distribution of 0.19 and 0.43 L/kg and terminal half-life of 30 min. 4.  The average absolute bioavailability of nor-NOHA after i.p. and i.t. delivery was 98% and 53%, respectively. The absorption from the airways was rate-limiting and its extent decreased with the dose. 5.  In conclusion, nor-NOHA is rapidly cleared from the plasma in concordance with the short time window of its in vivo inhibitory activity reported in the literature. I.t. instillation of aerosol for topical effects of nor-NOHA in the airways is characterized with significant systemic availability.

This study investigated the protective effect of two nitric oxide synthase inhibitors Nω-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 (NOx) 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 NOx 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 NOx 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.