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Methylene Blue Administration During and After Life-Threatening Intoxication by Hydrogen Sulfide: Efficacy Studies in Adult Sheep and Mechanisms of Action.
Toxicol Sci 2019; 168(2):443-459TS

Abstract

Exposure to toxic levels of hydrogen sulfide (H2S) produces an acute cardiac depression that can be rapidly fatal. We sought to characterize the time course of the cardiac effects produced by the toxicity of H2S in sheep, a human sized mammal, and to describe the in vivo and in vitro antidotal properties of methylene blue (MB), which has shown efficacy in sulfide intoxicated rats. Infusing NaHS (720 mg) in anesthetized adult sheep produced a rapid dilation of the left ventricular with a decrease in contractility, which was lethal within about 10 min by pulseless electrical activity. MB (7 mg/kg), administered during sulfide exposure, maintained cardiac contractility and allowed all of the treated animals to recover. At a dose of 350 mg NaHS, we were able to produce an intoxication, which led to a persistent decrease in ventricular function for at least 1 h in nontreated animals. Administration of MB, 3 or 30 min after the end of exposure, whereas all free H2S had already vanished, restored cardiac contractility and the pyruvate/lactate (P/L) ratio. We found that MB exerts its antidotal effects through at least 4 different mechanisms: (1) a direct oxidation of free sulfide; (2) an increase in the pool of "trapped" H2S in red cells; (3) a restoration of the mitochondrial substrate-level phosphorylation; and (4) a rescue of the mitochondrial electron chain. In conclusion, H2S intoxication produces acute and long persisting alteration in cardiac function in large mammals even after all free H2S has vanished. MB exerts its antidotal effects against life-threatening sulfide intoxication via multifarious properties, some of them unrelated to any direct interaction with free H2S.

Authors+Show Affiliations

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania.Division of Pulmonary and Critical Care Medicine, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania.Center of Translational Medicine. Department of Medicine, Lewis Katz School of Medicine of Temple University, Philadelphia, Pennsylvania.Heart and Vascular Institute, Pennsylvania State University College of Medicine, Hershey, Pennsylvania.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

30590764

Citation

Haouzi, Philippe, et al. "Methylene Blue Administration During and After Life-Threatening Intoxication By Hydrogen Sulfide: Efficacy Studies in Adult Sheep and Mechanisms of Action." Toxicological Sciences : an Official Journal of the Society of Toxicology, vol. 168, no. 2, 2019, pp. 443-459.
Haouzi P, Tubbs N, Cheung J, et al. Methylene Blue Administration During and After Life-Threatening Intoxication by Hydrogen Sulfide: Efficacy Studies in Adult Sheep and Mechanisms of Action. Toxicol Sci. 2019;168(2):443-459.
Haouzi, P., Tubbs, N., Cheung, J., & Judenherc-Haouzi, A. (2019). Methylene Blue Administration During and After Life-Threatening Intoxication by Hydrogen Sulfide: Efficacy Studies in Adult Sheep and Mechanisms of Action. Toxicological Sciences : an Official Journal of the Society of Toxicology, 168(2), pp. 443-459. doi:10.1093/toxsci/kfy308.
Haouzi P, et al. Methylene Blue Administration During and After Life-Threatening Intoxication By Hydrogen Sulfide: Efficacy Studies in Adult Sheep and Mechanisms of Action. Toxicol Sci. 2019 04 1;168(2):443-459. PubMed PMID: 30590764.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Methylene Blue Administration During and After Life-Threatening Intoxication by Hydrogen Sulfide: Efficacy Studies in Adult Sheep and Mechanisms of Action. AU - Haouzi,Philippe, AU - Tubbs,Nicole, AU - Cheung,Joseph, AU - Judenherc-Haouzi,Annick, PY - 2020/04/01/pmc-release PY - 2018/12/28/pubmed PY - 2018/12/28/medline PY - 2018/12/28/entrez KW - Hydrogen Sulfide Intoxication KW - Methylene Blue KW - Toxic Cardiac Failure SP - 443 EP - 459 JF - Toxicological sciences : an official journal of the Society of Toxicology JO - Toxicol. Sci. VL - 168 IS - 2 N2 - Exposure to toxic levels of hydrogen sulfide (H2S) produces an acute cardiac depression that can be rapidly fatal. We sought to characterize the time course of the cardiac effects produced by the toxicity of H2S in sheep, a human sized mammal, and to describe the in vivo and in vitro antidotal properties of methylene blue (MB), which has shown efficacy in sulfide intoxicated rats. Infusing NaHS (720 mg) in anesthetized adult sheep produced a rapid dilation of the left ventricular with a decrease in contractility, which was lethal within about 10 min by pulseless electrical activity. MB (7 mg/kg), administered during sulfide exposure, maintained cardiac contractility and allowed all of the treated animals to recover. At a dose of 350 mg NaHS, we were able to produce an intoxication, which led to a persistent decrease in ventricular function for at least 1 h in nontreated animals. Administration of MB, 3 or 30 min after the end of exposure, whereas all free H2S had already vanished, restored cardiac contractility and the pyruvate/lactate (P/L) ratio. We found that MB exerts its antidotal effects through at least 4 different mechanisms: (1) a direct oxidation of free sulfide; (2) an increase in the pool of "trapped" H2S in red cells; (3) a restoration of the mitochondrial substrate-level phosphorylation; and (4) a rescue of the mitochondrial electron chain. In conclusion, H2S intoxication produces acute and long persisting alteration in cardiac function in large mammals even after all free H2S has vanished. MB exerts its antidotal effects against life-threatening sulfide intoxication via multifarious properties, some of them unrelated to any direct interaction with free H2S. SN - 1096-0929 UR - https://www.unboundmedicine.com/medline/citation/30590764/Methylene_Blue_Administration_During_and_After_Life_Threatening_Intoxication_by_Hydrogen_Sulfide:_Efficacy_Studies_in_Adult_Sheep_and_Mechanisms_of_Action_ L2 - https://academic.oup.com/toxsci/article-lookup/doi/10.1093/toxsci/kfy308 DB - PRIME DP - Unbound Medicine ER -