Effect of a free radical scavenger on nitric oxide release in microvessels

BackgroundSuperoxides impair nitric oxide (NO) bioactivity; however, the dynamics of NO release in the peripheral microcirculation remain unknown. We investigated the effect of a free-radical scavenger (edaravone) on dynamic NO release and the expression of eNOS and iNOS in microvessels.Methods and resultsAn electrochemical microsensor was positioned at the iliac artery bifurcation of the rat abdominal aorta, and NO release was measured in response to edaravone. A bio-imaging model was also used to obtain images of NO release from microvessels. Moreover, eNOS expression and iNOS expression were investigated in inflammatory and non-inflammatory models. NO was observed in association with microvessels in the mesentery. NO release in the aorta was significantly greater with edaravone than with placebo in the non-inflammatory model (P < 0.05). Acetylcholine-induced NO release with edaravone was greater than with placebo in both models. Bio-imaging showed greater NO release from arterioles than from venules. eNOS expression with edaravone was greater than with placebo with or without inflammation. iNOS expression was increased by inflammation, but edaravone inhibited this increase.ConclusionThese results support the critical role of NO in the microcirculation and suggest that free-radical scavenging increases the bioavailability of NO in the microcirculation via eNOS upregulation.     

Syntheses and SH-enzyme inhibitory activities of new epoxysuccinic acid piperazine derivatives against mu-calpain and cathepsin B.

New chiral epoxysuccinic acid derivatives 5 approximately 23 bearing various amino acids and N-substituted piperazines were synthesized to evaluate their inhibitory activities against mu-calpain and cathepsin B. After screening these compounds, 1-[(2S,3S)-epoxysuccinyl-L-leucyl]-4-(2-chlorophenyl)piperazine 9 proved to exhibit fairly strong inhibitory activity against both cysteine proteases. L-Valyl derivative 19 exhibited selective inhibitory activity against cathepsin B in comparison with that against mu-calpain.     

Developmental toxicity of the topoisomerase inhibitor, etoposide, in rabbits after intravenous administration.

The developmental effect of the topoisomerase inhibitor, etoposide, was investigated in pregnant rabbits given intravenous doses during early organogenesis. Does received 0, 0.25, 0.5, 1, or 2 mg/kg/day on days 7 through 9 of gestation. Fetal parameters were evaluated on day 28 of gestation. Live fetuses were examined for gross, visceral, and skeletal malformations and variations. In addition, telencephalon in embryos 8 h following the final treatment was examined histologically. No change in general condition was observed in any does, but a significant decrease in body weight gain during the pregnancy and enlargement of the liver resulting from marked fatty change were observed in does treated with etoposide at 2 mg/kg/day. Etoposide had neither lethal nor growth retarded effects on embryos/fetuses. However, axial skeletal malformation and extra ribs had a low incidence but were significant in the group treated with etoposide at 2 mg/kg/day, whereas no significant increases in external malformations in term fetuses nor in pyknotic cells in the ventricular zone of telencephalon in embryos were noticed in any etoposide-treated groups. It was concluded that anatomical defects (skeletal malformation or variation) in rabbits were induced by intravenous etoposide treatment during early organogenesis and that they occurred in the presence of maternal toxicity.     

Induction of intestinal tumors and lymphomas in C57BL/6N mice by a food-borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.

2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant heterocyclic amine contained in cooked meat and fish. Although PhIP has been demonstrated to induce various types of tumors in rats, lymphomas predominated in mice using the CDF1 strain. To investigate the carcinogenic activity of PhIP on other organs in mice with a different genetic background, PhIP was administered to C57BL / 6N mice. After a 40-week administration of 300 ppm of PhIP in a high-fat diet followed by continuous feeding with a high fat diet, C57BL / 6N mice developed adenomas and adenocarcinomas in the small intestine, the incidences being 52% in males and 68% in females at weeks 95 and 70, respectively. Lymphomas of B-cell origin also developed in both sexes as frequently as in the CDF1 strain, incidences being 48% in males and 32% in females. Although the incidence in PhIP-treated female mice did not differ from that in the control mice, lymphomas developed significantly earlier in the PhIP-treated mice. The present study demonstrated that the intestinal tract is another potential target of PhIP-induced carcinogenesis in mice, and that the carcinogenic activity of PhIP could be affected by the genetic background of the animals.