H₂S induced coma and cardiogenic shock in the rat: Effects of phenothiazinium chromophores

Abstract

Context. 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. Objectives. 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. Materials and 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/dt_max 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. Conclusion. 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.

Keywords:

• Hydrogen sulfide
• Pulseless electrical activity
• Cardiac function
• Methylene blue
• Azure B

Acknowledgements

The authors are grateful to Ms. Nicole Tubbs for her skillful technical assistance. This work has been supported by the CounterACT Program, National Institutes of Health Office of the Director (NIH OD), and the National Institute of Neurological Disorders and Stroke (NINDS), Grant Numbers: 1R21NS080788-01 and 1R21NS090017-01.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.