title: H2S induced coma and cardiogenic shock in the rat: Effects of phenothiazinium chromophores.
abstract: BACKGROUND
  Hydrogen sulfide (H2S) intoxication produces an acute depression in cardiac contractility-induced circulatory failure, which has been shown to be one of the major contributors to the lethality of H2S intoxication or to the neurological sequelae in surviving animals. Methylene blue (MB), a phenothiazinium dye, can antagonize the effects of the inhibition of mitochondrial electron transport chain, a major effect of H2S toxicity.
  
  
  OBJECTIVE
  We investigated whether MB could affect the immediate outcome of H2S-induced coma in un-anesthetized animals. Second, we sought to characterize the acute cardiovascular effects of MB and two of its demethylated metabolites-azure B and thionine-in anesthetized rats during lethal infusion of H2S.
  
  
  METHODS
  First, MB (4 mg/kg, intravenous [IV]) was administered in non-sedated rats during the phase of agonal breathing, following NaHS (20 mg/kg, IP)-induced coma. Second, in 4 groups of urethane-anesthetized rats, NaHS was infused at a rate lethal within 10 min (0.8 mg/min, IV). Whenever cardiac output (CO) reached 40% of its baseline volume, MB, azure B, thionine, or saline were injected, while sulfide infusion was maintained until cardiac arrest occurred.
  
  
  RESULTS
  Seventy-five percent of the comatose rats that received saline (n = 8) died within 7 min, while all the 7 rats that were given MB survived (p = 0.007). In the anesthetized rats, arterial, left ventricular pressures and CO decreased during NaHS infusion, leading to a pulseless electrical activity within 530 s. MB produced a significant increase in CO and dP/dtmax for about 2 min. A similar effect was produced when MB was also injected in the pre-mortem phase of sulfide exposure, significantly increasing survival time. Azure B produced an even larger increase in blood pressure than MB, while thionine had no effect.
  
  
  CONCLUSIONS
  MB can counteract NaHS-induced acute cardiogenic shock; this effect is also produced by azure B, but not by thionine, suggesting that the presence of methyl groups is a prerequisite for producing this protective effect.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Pennsylvania State University, College of Medicine , Hershey, PA , USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sonobe
authors.forename: Philippe
authors.initials: P
authors.lastname: Haouzi
mesh_terms: D000818:Animals; D000931:Antidotes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001399:Azure Stains / Q000494:pharmacology; D001711:Biotransformation; D002302:Cardiac Output / Q000187:drug effects; D002316:Cardiotonic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D003128:Coma / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D006862:Hydrogen Sulfide; D008297:Male; D008751:Methylene Blue / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010640:Phenothiazines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D012770:Shock, Cardiogenic / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D013329:Structure-Activity Relationship; D013440:Sulfides; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D000931:Antidotes; D001399:Azure Stains; D002316:Cardiotonic Agents; D010640:Phenothiazines; D013440:Sulfides; C025819:Azure B; C025451:sodium bisulfide; D008751:Methylene Blue; C009469:thionine; D006862:Hydrogen Sulfide
keywords: Azure B; Cardiac function; Hydrogen sulfide; Methylene blue; Pulseless electrical activity