Inhibition of DNA repair synthesis in the rat by in vivo exposure to psychotropic drugs and reversal of the effect by co-administration with alpha-tocopherol

Changes in unscheduled DNA synthesis (UDS) in lymphocytes and lipid peroxidation (LPO) in the rat brain regions cortex, hippocampus and hypothalamus were studied after 12 months of treatment with the neuroleptic fluphenazine (5 mg/kg b.w.), lithium (0.05% in drinking water), alpha-tocopherol (alpha-TP, 0.01% in drinking water) and the anticholinergic drug 7-methoxytacrine (0.1 and 1.0 g/kg in the diet). Fluphenazine and lithium suppressed UDS and increased LPO in cortex and hypothalamus. 7-Methoxy-tacrine at the lower dose stimulated UDS, at the higher dose it suppressed UDS after 6 months of exposure. Simultaneous administration of alpha-TP with fluphenazine suppressed the increase in LPO and the decrease in UDS produced by the neuroleptic alone. alpha-TP plasma levels were increased in groups administered alpha-TP as well as the levels in the hippocampus. Results indicate that the damage of biomembranes and the DNA repair enzymatic system as a consequence of fluphenazine action may be eliminated by the simultaneous administration of alpha-TP.     

Effect of heparin on the antiradiation activity of cystamine, decreasing with a reduction in radiation intensity

It was shown that a single injection of heparin (250 units/kg) 15 min and 24 h before irradiation potentiated a slight radioprotective effect of cystamine (dichlorohydrate, 170 mg/kg) which was registered after the administration thereof to mice 30 min before irradiation with an absolutely lethal dose at a dose rate of 0.0025 Gy/c.     

Selenium Pretreatment Enhances the Radioprotective Effect and Reduces the Lethal Toxicity of Wr-2721

Although WR-2721, S-2-(3-aminopropylamino)ethylphosphorothioic acid, is an effective radioprotector, its use is limited by its toxicity. Combining WR-2721 with other agents might decrease its toxicity and/or increase its effectiveness. The effect of selenium (Se) pretreatment on the acute toxicity and radioprotective effect of WR-2721 was studied in male CD2F1 mice. Injection of 1.6mg/kg Se 24 hr before WR-2721 (800-1200 mg/kg, IP) decreased the lethality of WR-2721 significantly. Lower doses of Se were also effective, but simultaneous administration was not effective. Se injection alone (1.6 mg/kg) 24 hr before cobalt-60 irradiation increased the survival (dose reduction factor, DRF = 1.1) significantly. A synergistic effect on post-irradiation survival was observed when Se was injected 24 hr before WR-2721 (200-600 mg/ kg IP before irradiation). For example, after exposure to 22 Gy (1 Gy/min), 30-day survival was 100% when mice were treated with both Se and 600mg/kg WR-2721, and was 13% with WR-2721 alone. The DRF after 400 mg/kg WR-2721 was 2.6 with Se compared to 2.2 without Se pretreatment. Alkaline phosphatase activity in bone marrow cells and serum was significantly depressed after treatment with 1.6 mg/kg Se, suggesting that a retardation of conversion of WR-2721 to its active free sulfhydryl form through the action of alkaline phosphatase might be partly responsible for the effects of Se. Other possible mechanisms related to the antioxidant properties of Se are under investigation.     

Selenium Pretreatment Enhances the Radioprotective Effect and Reduces the Lethal Toxicity of Wr-2721

Although WR-2721, S-2-(3-aminopropylamino)ethylphosphorothioic acid, is an effective radioprotector, its use is limited by its toxicity. Combining WR-2721 with other agents might decrease its toxicity and/or increase its effectiveness. The effect of selenium (Se) pretreatment on the acute toxicity and radioprotective effect of WR-2721 was studied in male CD2F1 mice. Injection of 1.6mg/kg Se 24 hr before WR-2721 (800-1200 mg/kg, IP) decreased the lethality of WR-2721 significantly. Lower doses of Se were also effective, but simultaneous administration was not effective. Se injection alone (1.6 mg/kg) 24 hr before cobalt-60 irradiation increased the survival (dose reduction factor, DRF = 1.1) significantly. A synergistic effect on post-irradiation survival was observed when Se was injected 24 hr before WR-2721 (200-600 mg/ kg IP before irradiation). For example, after exposure to 22 Gy (1 Gy/min), 30-day survival was 100% when mice were treated with both Se and 600mg/kg WR-2721, and was 13% with WR-2721 alone. The DRF after 400 mg/kg WR-2721 was 2.6 with Se compared to 2.2 without Se pretreatment. Alkaline phosphatase activity in bone marrow cells and serum was significantly depressed after treatment with 1.6 mg/kg Se, suggesting that a retardation of conversion of WR-2721 to its active free sulfhydryl form through the action of alkaline phosphatase might be partly responsible for the effects of Se. Other possible mechanisms related to the antioxidant properties of Se are under investigation.     

The antiradiation properties of the ecdysteroid-containing compounds

The antiradiation properties of the ecdysteroid-containing preparations ("serpisten" and inokosterone) are studied under their application before or after the 22.6 cGy chronic low intensity gamma-irradiation of mice. It is shown that the antiradiation of these compounds depend on the dose of preparations and time of the application before or after irradiation of mice. "Serpisten" prevented the decrease of the growth of the body mass of irradiated mice. The normalization of the phospholipid composition of the mice liver and blood erythrocytes for the most investigated parameters revealed under the application of this compound at the dose of 50 mg/kg after the irradiation of animals. The capacity of "serpisten" to decompose of peroxides is shown in vitro. Inokosterone had the certain anabolic properties, caused the normalization of the total peroxidase activity of blood and intensity of the lipid peroxidation (LPO) in brain and in liver, and also the repair of the interrelation between the LPO intensity and catalase activity in the irradiated mice liver. The obtained results allow to conclude that the antiradiation properties of the ecdysteroid-containing preparations under the chronic low intensity irradiation of animals at the low dose due to their capacity to depend on the LPO regulatory system parameters.     

Multi-endpoint biological monitoring of phosphine workers

5-Aminosalicylic acid (5ASA), a prescribed drug for ulcerative colitis, is a potent scavenger of oxygen-derived free radicals. The present study was undertaken to ascertain its ability to protect against radiation-induced damage. The drug dose-dependent effect, optimum time of drug administration and radiation dose-dependent effect (0-4 Gy) on in vivo radiation protection against micronuclei induction in polychromatic erythrocytes (PCE) and normochromatic erythrocytes (NCE) were studied in the bone marrow of mice. Intraperitoneal injection of 10-125 mg/kg of the drug 30 min before whole body irradiation with 3 Gy produced a significant reduction in the frequency of micronucleated erythrocytes at 24 h after exposure. The optimum dose for protection without drug toxicity was 25 mg/kg body weight. Injection of 25 mg/kg of the drug 60 or 30 min before or within 15 min after 3 Gy whole body gamma-irradiation resulted in a significant decrease in the radiation-induced PCE and NCE with micronuclei (MPCE and MNCE) and an increase in the ratio of PCE to NCE (P/N), at 24 h post-irradiation. Maximum effect was seen when the drug was administered 30 min before irradiation. Therefore, to study the radiation dose-response, mice were pre-treated with 25 mg/kg of 5ASA 30 min before 1-4 Gy of gamma-irradiation. Radiation increased the MN frequency linearly (r(2)=0.99) with dose. Pre-treatment with 5ASA significantly reduced the MN counts to 40-50% of the radiation (RT) alone values, giving a dose modification factor (DMF) of 2.02 (MPCE) and 2.53 (MNCE). Irradiation resulted in a dose-dependent decline in the P/N ratio at all the doses of radiation studied. 5ASA produced a significant increase in the P/N ratio from that of irradiated controls, at all doses of radiations tested. These results show that 5ASA protect mice against radiation-induced MN formation and mitotic arrest.     

In vivo radioprotection by alpha-TMG: preliminary studies

alpha-TMG is a novel water-soluble derivative of Vitamin E that has shown excellent antioxidant activity. The parent compound has demonstrated protection against radiation induced chromosomal damage in vivo. Hence, the preliminary experiments to determine the radioprotective activity of alpha-TMG were carried out in adult Swiss albino mice. Acute toxicity of the drug was studied taking 24h, 72 h and 30 day mortality after a single intraperitoneal injection of 500-2000 mg/kg body weight of the drug. The drug LD(50) for 24h and 72 h/30 day survival were found to be 1120 and 1000 mg/kg body weight, respectively. The optimum time of drug administration and drug dose-dependent effect on in vivo radiation protection of bone marrow chromosomes was studied in mice. Injection of 600 mg/kg of the drug 15 min before or within 5, 15 or 30min after 3Gy whole body gamma radiation resulted in a significant decrease in the aberrant metaphases percent at 24h post-irradiation; the maximum effect was seen when the drug was given immediately after irradiation. Injection of 200-800 mg/kg TMG within 5 min of irradiation with 3 Gy produced a significant dose-dependent reduction in the radiation induced percent aberrant metaphases and in the frequency of micronucleated erythrocytes at 24h after exposure, with a corresponding decrease in the different types of aberrations. The optimum dose for protection without drug toxicity was 600 mg/kg body weight. At this dose, TMG produced 70 and >60% reduction in the radiation induced percent aberrant metaphases and micronucleated erythrocytes, respectively. The high water solubility and effectiveness when administered post-irradiation favor TMG as a likely candidate for protection in case of accidental exposures.     

Parameters of proliferative activity of hematopoietic cells in mice protected from irradiation by indralin in combination with Zn-metallothionein

One day after the irradiation (dose 6 Gy) of mice protected by the injection of Zn-metallothionein (Zn-MT) in doze 8.6 mg/kg, 10-20 min before irradiation, then alpha-adrenomimetic indraline (150 mg/kg) 5-10 min before irradiation the increase in nucleic cell number, [3H] thymidine incorporation, and antioxidant activity in bone marrow in comparison with the control and indraline per se was revealed. In mice protected according to the scheme: Zn-MT in the same doze, then indraline (100 mg/kg) one day after, and then in 5-10 min exposure to 6 Gy it was found more than 9 times increase of endogeneous CFC in spleen on 8th day while indraline per se raised CFC number only 4.8 times. It was found that Zn-MT reduce the indraline acute toxicity. The data on radioprotective activity of monomeric and polymeric Zn-MT forms are submitted.     

Postirradiation glucan administration enhances the radioprotective effects of WR-2721

Based on murine survival studies, endogenous hemopoietic spleen colony formation (E-CFU), and recovery of bone marrow and splenic granulocyte-macrophage colony-forming cells (GM-CFC), it was demonstrated that the postirradiation administration of glucan, an immunomodulator and hemopoietic stimulant, enhances the radioprotective effects of WR-2721. LD50/30 dose reduction factors for mice treated with WR-2721 (200 mg/kg approximately 30 min before irradiation), glucan (250 mg/kg approximately 1 h after irradiation), or both agents were 1.37, 1.08, and 1.52, respectively. Enhanced survival in mice treated with both agents appeared to be due in part to glucan's ability to accelerate hemopoietic regeneration from stem cells initially protected from radiation-induced lethality by WR-2721. Following a 10-Gy radiation exposure, E-CFU numbers in mice treated with saline, WR-2721, glucan, or both WR-2721 and glucan were 0.05 +/- 0.03, 6.70 +/- 1.05, 0.95 +/- 0.24, and 33.90 +/- 2.96, respectively. Similarly, bone marrow and splenic GM-CFC numbers were greater in mice treated with both WR-2721 and glucan than in mice treated with either agent alone. These results demonstrated at least additive radioprotective effects when mice were given WR-2721 prior to irradiation and glucan following irradiation. These effects appeared to depend on the sequential cell protection mediated by WR-2721 and hemopoietic repopulation mediated by glucan.     

Protection by WR-3689 against gamma-ray-induced intestinal damage: comparative effect on clonogenic cell survival, mouse survival, and DNA damage

The aminophosphorothioate WR-3689 was characterized for its ability to protect mouse jejunal cells in vivo from single doses of X or gamma radiation. First, the effect of the drug on the survival of jejunal stem cells was examined using a clonogenic end point, the crypt microcolony assay. When WR-3689 was administered 30 min prior to whole-body irradiation, the number of surviving crypt cells was markedly increased at all doses of the drug, although protection began to level out at doses larger than 600 mg/kg. Protection was maximal when the drug was given 30 min before whole-body irradiation and declined rapidly with both shorter and longer intervals. Protection factors (PFs) were obtained by measuring survival curves for clonogenic crypt cells as a function of radiation dose; WR-3689 given 30 min before whole-body irradiation protected jejunum in the microcolony assay with a PF of 1.26 +/- 0.02, 1.50 +/- 0.10, and 1.65 +/- 0.10 at doses of 200, 400, and 800 mg/kg, respectively. Next, the effect of WR-3689 on the survival of jejunal stem cells was determined by assaying the survival of mice given X-ray doses to the whole abdomen in the range leading to death from the gastrointestinal syndrome. The PFs based on the LD50 values for 11-day survival were 1.31 +/- 0.05 (200 mg/kg) and 1.48 +/- 0.05 (400 mg/kg). Crypt-cell survival and animal survival were thus modified to a similar extent by this agent. Finally, the effect of WR-3689 on the induction of DNA single-strand breaks (SSBs) in jejunal cells was measured using an adaptation of the alkaline elution methodology. In mice treated with WR-3689 (400 or 800 mg/kg) 30 min prior to whole-body irradiation with 10 Gy there was no significant reduction in the number of DNA SSBs induced either in samples of the jejunum or in the cycling crypt cells, providing further evidence that there is no simple relationship between the modification of DNA SSBs and the survival of jejunal stem cells.     

Antitumor effect of photodynamic therapy with zincphyrin, zinc-coproporphyrin III, in mice

We studied the antitumor effects of photodynamic therapy (PDT) with Zincphyrin, coproporphyrin III with zinc, derived from Streptomyces sp. AC8007, in vitro and in vivo. The photokilling effect of Zincphyrin in the presence of 0.78-100 microg/ml with visible light of 27.2 mW x min/cm2 for 10 min was lower than the hematoporphyrin (Hp) used as a control with L5178Y or sarcoma-180 cells. On the other hand, Zincphyrin apparently reduced tumor growth after intraperitoneal injection at doses of 12.5-50 mg/kg with light irradiation of 75.48 mW x min/cm2 for 10 min in sarcoma-180-bearing mice. Although no mice treated with Zincphyrin died, Hp did cause the death of mice. In B-16 melanoma-bearing mice, both Zincphyrin and Hp had a similar phototherapic effect. Further improvement of the phototherapic effect was observed with the continuous administration of Zincphyrin at 12.5 mg/kg per day for 3 days. The concentration of Zincphyrin in the serum reached a maximum level of 16 microg/ml within 20 min, and the concentration remained at 4.2 microg/ml at 1 hour after the onset of treatment, indicating its rapid action in the body. No animals died after the intraperitoneal administration of Zincphyrin at 100 mg/kg plus exposure to light of 10 mW x min/cm2 for 2 hours, and the body weight of the mice did not decrease. In contrast, all animals receiving 100 mg/kg of Hp under the same conditions died. These results indicate that Zincphyrin would be a useful photosensitizer with low phototoxicity.     

Effect of subtherapeutic doses of docetaxel (taxotere) on the efficacy of radiotherapy and pro-oxidant-antioxidant balance in rats with Guerin's carcinoma

In the experiments at Wistar male rats the effect of subtherapeutic doses of docetaxel (5 and 10 mg/kg) on the radiotherapy efficacy (20 Gy of single-dose X-rays) namely growth rate of Guerin's tumor and prooxidant-antioxidant balance in liver and blood of animals bearing tumors was investigated. It has been demonstrated that docetaxel at dose 5 mg/kg given 18 hours before irradiation resulted in significant tumor growth delay (2.3-2.7-fold) in comparison with group of rats that received only irradiation. After application of higher dose of docetaxel there was no statistically significant change of tumor size along the whole experiment (14 and 21 days after tumor implantation). Content of lipid peroxidation products was revealed to be considerably increased after chemotherapy and concurrent irradiation when docetaxel was used in a dose of 10 mg/kg. At the same time glutatione peroxidase activity and antioxidative activity of blood plasma were reduced. In the rat liver chemoradiotherapy led to decrease of glutathion peroxidase and glutathione-S-transferase activity to greater degree at docetaxel dose of 10 mg/kg. The obtained results allow to conclude that higher dose of docetaxel and concurrent irradiation resulted in the most effective Guerin's carcinoma growth delay and considerable deviation of antioxidant-prooxidant balance of tissues in the direction of the last.     

Synthesis,radioprotective activity and pharmacokinetics characteristic of a new stable nitronyl nitroxyl radical-NIT2011

A new stable nitronyl nitroxyl radical NIT2011 was synthesized and characterized. The radioprotective effect and pharmacokinetics profiles of NIT2011 were investigated. The results showed that when irradiation exposure dose was 6.5 Gy gama radiation, the survival rate in the irradiation-only group was 20% on 30th day. The survival rate was 70%, 80%, and 90% on 30th day when mice were pretreated with 0.25, 0.5 and 1.0 mmol/kg NIT2011, respectively. The pretreatment of NIT2011 increased number of spleen colonies, the numbers of bone marrow cells and protein level in bone marrow cells. Pretreatment with NIT2011 prior to radiation exposure increased the plasma SOD (superoxide dismutase) activity. 24 h after irradiation exposure, level of plasma MDA (malondialdehyde) in irradiation-only mice was 14.8 ± 2.8 nmol/mL, level of plasma MDA in NIT2011 (1 mmol/kg) pretreated mice was 9.8 ± 2.0 nmol/mL. Three days after irradiation exposure, the micronucleus ratio in irradiation-only mice is 40.2 ± 3.6, the micronucleus ratio in NIT2011 (1 mmol/kg) pretreated mice was 11.7 ± 1.2. NIT2011 was easily absorbed in mice after it was oral administrated. Compared with the intraperitoneal injection, the relative oral bioavailability of the NIT2011 was 27.5% in mice. The LD₅₀ of NIT2011 was 1510 mg/kg in mice by oral administration. Thus, NIT2011 has potential in being developed as an oral dosage form, safe and effective radioprotective agent.     

Effect of lysozyme on hepatocyte resistance

Antitoxic effect of lysozyme was shown on a model of experimental acute toxic hepatitis of rats and mice. Administration of lysozyme to the animals in a dose of 5 mg/kg 24 hours before administration of carbon tetrachloride markedly decreased the level of morphological damages in the liver tissue and promoted a decrease in increased levels of alanine aminotransferase in blood serum. Higher levels of lysozyme in blood serum and cells of mouse peritoneal exudate 3 hours after administration of lysozyme were observed. The role of lysozyme as one of the main products secreted by activated macrophages in providing the general and antitoxic resistance of hepatocytes is discussed. Possible use of lysozyme as a hepatoprotective agent is suggested.     

Inhibition of cyclooxygenase 2 in mice increases production of g-csf and induces radioprotection

Meloxicam, a selective inhibitor of cyclooxygenase 2, was tested to determine its ability to modulate hematopoiesis and to influence survival of mid-lethally gamma-irradiated mice. A single dose of meloxicam (20 mg/kg) administered to mice intraperitoneally 1 h before irradiation was shown to enhance serum levels of granulocyte colony-stimulating factor (G-CSF) during the first 24 h after irradiation, to elevate numbers of granulocytic precursor cells in bone marrow and granulocyte counts in peripheral blood on day 10 after irradiation, and to increase 30-day survival of these mice. The results provide new evidence for the protective ability of meloxicam administration to mice irradiated with mid-lethal doses and contribute to the understanding of the mechanisms of this meloxicam action by drawing attention to the possible role of increased endogenous G-CSF production.     

Multiple subcutaneous injections of somatostatin induce tachyphylaxis of the suppression of plasma insulin, but not glucagon, in the rat

The time course of pancreatic effects of somatostatin was studied over a period of 2 h in unanesthetized unrestrained rats after administration of the peptide by intravenous infusion and by single and multiple subcutaneous injections. During infusion of 10 and 30 micrograms/kg per min, somatostatin continuously suppressed plasma insulin and plasma glucagon. Plasma glucose was significantly increased at the lower dose, but not affected at the higher dose. Single subcutaneous injections of 0.3 and 3 mg/kg decreased plasma insulin and glucagon dose-dependently for 20-60 min without affecting plasma glucose. Multiple subcutaneous injections of somatostatin (one to four doses of 3 mg/kg, administered at intervals of 30 min) caused an initial decrease of plasma insulin (at 30 min), a rebound-increase at 60 and 90 min, and a final return to control values by 120 min. Plasma glucagon remained continuously suppressed. Plasma glucose increased significantly at 60 and 90 min and tended to return towards control values thereafter. In conclusion, pancreatic B cells - but not A cells - of the rat develop tachyphylaxis to somatostatin within 2 h after multiple subcutaneous injections of the peptide. By this mode of administration, 'selective' suppression of plasma glucagon can be achieved with somatostatin in the rat.     

Changes in the sensitivity of mice to the action of gamma irradiation by Viscum album L. polysaccharides]

The influence of water-soluble polysaccharides of Viscum album L. on the survival of mice subjected to whole-body gamma-irradiation has been investigated. Polysaccharides were shown to exert a radioprotective effect which was a function of both the radiation dose and the drug dose and time of its injection. The maximum radioprotective efficacy of polysaccharides was observed after their injection 15 min before irradiation. A single intraperitoneal administration of polysaccharides (25 mg/kg) before irradiation with LD50/30 and LD100/10-12 increased the 60-day survival rate up to 95% and 27% respectively. The postirradiation injection of polysaccharides prevented death of 80% of mice given LD50 and increased the average life expectancy of animals irradiated with absolutely lethal doses.     

Antinociceptive effects of morphine-6-glucuronide in homozygous MDR1a P-glycoprotein knockout and in wildtype mice in the hotplate test

Morphine-6-glucuronide (M6G), a major metabolite of morphine with agonist opioid-receptor activity, was reported to be a substrate of P-glycoprotein (P-gp). Inhibition of P-gp may thus result in higher brain uptake of M6G. The goal of this observer-blinded, placebo controlled study, was to compare the antinociceptive effects of M6G in homozygous P-gp knockout (mdr1a(-/-)) and wildtype (mdr1a(+/+)) mice. M6G was injected intraperitoneally as a single dose of 0, 0.5, 1, 2.5, 5, and 10 mg/kg. Eight P-gp knockout and eight wildtype mice were studied per dose. A hot plate test was performed before and 5, 15, 30, 60, 90, 120, and 150 min after M6G administration. Plasma-concentrations of M6G, morphine, and morphine-3-glucuronide (M3G) were measured after intraperitoneal injection of 5 mg/kg M6G in another 14 P-gp knockout and 14 wildtype mice. No difference neither in the dose response relationship, nor in the time course of response latency times were observed between P-gp knockout and wildtype mice. However, latency times increased with higher doses of M6G, with antinociception significantly different from placebo at a M6G dose of 5 and 10 mg/kg. P-gp knockout mice tended to have higher plasma concentrations than the wildtype. However, plasma concentrations widely overlapped between groups and therefore no statistical significant group difference could be detected. We conclude that despite reported doubling of M6G brain uptake, absence of mdr1a coded P-gp does not enhance antinociceptive effects of M6G in the hotplate test after acute single-dose administration in mdr1a(-/-) knockout mice.     

Antihypertensive effect of total flavonoid fraction of Astragalus complanatus in hypertensive rats

The purpose of the present study was to quantify the antihypertensive effect of the total flavonoid (TF), extracted from the seed of Astragalus complanatus R. Brown, and to observe its effect on the renin-angiotensin system (RAS) in both renal hypertensive rats (RHR) and spontaneously hypertensive rats (SHR). RHR were created by the two-kidney one clip (2K1C) method. Systolic blood pressure was measured in conscious rats by the tail-cuff method. Plasma angiotensin II (AngII) and plasma renin activity (PRA) were measured with radioimmunoassay at 60 min after drug administration. The effects of TF on cardiac hemodynamics were also recorded in anesthetized RHR and SHR. TF was given by oral administration in low dose (100 mg/kg) and high dose (200 mg/kg) respectively. Compared to pre-administration control, TF induced an obvious decrease in systolic blood pressure in conscious normotensive Wistar rat, RHR and SHR. In the three groups the systolic blood pressure reached the lowest value at 60 min after TF. TF also induced a significant decrease in blood pressure in anesthetized RHR and SHR. At 60 min after treatment of TF, mean arterial pressure in high dose group (200 mg/kg) was decreased by 17% in RHR and by 17% in SHR respectively (P < 0.01). The depressor effect of TF lasted for at least 60 min. Cardiac output, heart rate and +/- dp/dtmax did not change. Conversely, total peripheral resistance was significantly decreased. The decrease in plasma AngII was found in both RHR and SHR. On the contrary, PRA increased at the same time. These findings suggested that TF is effective in reducing blood pressure in both RHR and SHR. The antihypertensive action of TF was attributed to a decrease in TPR secondary to a decrease in plasma concentration of AngII caused by TF.     

The effect of carnosine on the liver enzyme system in the irradiated body]

The effect of carnosine on post-radioactive changes in lipid peroxidation (LPO) products in blood serum and cytochrome P-450 content in liver microsomes has been studied. Per os administration of carnosine 24 hours prior to irradiation in a minimal lethal dose (7 Gr) markedly decreases the post-radioactive accumulation of LPO products in rat blood serum one hour after irradiation and fully restores the post-radioactive decrease in the cytochrome P-450 content in rat liver microsomes on day 5 after irradiation. Besides, the ability of carnosine to prevent the post-radioactive decline in the activity of UDP-glucuronyl transferase. Another key enzyme of the liver detoxifying system, has been demonstrated. The data obtained testify to the ability of carnosine to provide effective protection against post-radioactive intensification of LPO in irradiated organisms.