An impairment of the survival of mice subjected to whole-body gamma-irradiation with a lethal dose of 10 Gy and treated with a repeated postirradiation administration of prostaglandin synthesis inhibitors (PGSls), indomcthacin or diclofenac, was observed. Morphological examination of the gastrointestinal tract and the estimation of blood loss into its lumen in animals treated with diclofenac did not show serious damage such as haemorrhages or perforation, but revealed structural injury to the intestinal mucosa indicating inflammatory processes. The lesions found arc supposed to be connected with increased intestinal permeability which leads to endotoxin escape from the gut and a subsequent increased mortality rate of irradiated animals. It may be concluded that PGSls are not suitable for the management of radiation sickness after an exposure to lethal doses of ionizing radiation
Recent results of the authors have demonstrated that the elevation of extracellular adenosine induced by the combined administration of dipyridamole, a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate (AMP), a soluble adenosine prodrug, mediates radioprotective effects in mice. Furthermore, it has been shown that this action is induced by at least two mechanisms: (1) protection by hypoxia as a result of the effects of treatment on the cardiovascular system (bradycardia, vasodilation), and (2) an enhanced regeneration of the radiation-perturbed hematopoiesis. Here, it was ascertained that the joint use of an optimal dose of noradrenaline given with dipyridamole and AMP combination eliminates the hypothermic and hypoxic effects of the treatment, but preserves the radioprotective action of dipyridamole and AMP combination in terms of hematopoietic recovery and partially also survival enhancing effects of the drugs in gamma-irradiated mice. These findings might be of importance for attempts to obtain available and tolerable radioprotective pharmacological prescriptions for clinical use.