Our study was aimed at (1) determining the efficacy of the dye methylene blue (MB), following a rapidly lethal cyanide (CN) intoxication in un-sedated rats; (2) clarifying some of the mechanisms responsible for the antidotal properties produced by this potent cyclic redox dye. Sixty-nine awake rats acutely intoxicated by CN (IP, KCN 7 mg/kg) received saline, MB (20 mg/ kg) or hydroxocobalamin (HyCo, 150 mg/kg) when in deep coma. Survival in this model was very low, reaching 9% at 60 min without any treatment. Methylene blue significantly increased survival (59%, p < .001) at 60 min, versus 37% with HyCo (p < .01). In addition, 8 urethane-anesthetized rats were exposed to a sublethal CN intoxication (KCN, 0.75 mg/kg/min IV for 4 min); they received MB (20 mg/kg, IV) or saline, 5 min after the end of CN exposure. All MB-treated rats displayed a significant reduction in hyperlactacidemia, a restoration of pyruvate/lactate ratio-a marker of NAD/NADH ratio-and an increase in CO 2 production, a marker of the activity of the TCA cycle. These changes were also associated with a 2-fold increase in the pool of CN in red cells. Based on series of in vitro experiments, looking at the effects of MB on NADH, as well as the redox effects of MB on hemoglobin and cytochrome c, we hypothesize that the antidotal properties of MB can in large part be accounted for by its ability to readily restore NAD/NADH ratio and to cyclically re-oxidize then reduce the iron in hemoglobin and the electron chain complexes. All of these effects can account for the rapid antidotal properties of this dye following CN poisoning.
We have investigated the potential acute desensitizing role of the beta arrestin 2 (b-arr2) pathway on the ventilatory depression produced by levels of fentanyl ranging from analgesic to life-threatening (0.1 to 60 mg/kg IP) in control and b-arr2 deficient non-sedated mice. Fentanyl at doses of 0.1, 0.5 and 1 mg/kg IP - corresponding to the doses previously used to study the role of b-arr2 arrestin pathway - decreased ventilation, but along the V̇E/V̇CO2 relationship established in baseline conditions, which was therefore indistinguishable from animals that were immobile. Above 1.5 mg/kg, however, ventilation was depressed out of proportion of the changes in metabolism, suggesting a specific depression of the drive to breathe. The ventilatory responses were similar between the 2 groups. At high doses of fentanyl (60 mg/kg IP) one out of 20 control mice died by apnea versus 8 out of 20 b-arr2 deficient mice (P=0.008). In the surviving mice, ventilation was however identical in both groups. The ventilatory effects of fentanyl in b-arr2 deficient mice reported in the literature are primarily mediated by the "indirect" effects of sedation/hypometabolism on breathing control. There was an excess mortality at very high doses of fentanyl in the b-arr2 deficient mice, which mechanisms are still open to question, since the capacity of maintaining a rhythmic, although profoundly depressed, breathing activity remains similar in all of the surviving control and b-arr2 deficient mice.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.