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 unanesthetized 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/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. 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.

Circulatory Failure During Noninhaled Forms of Cyanide Intoxication

“…An additional source of air was introduced into the first mixing chamber in which flow was continuously measured using another pneumotachograph (1100 Series, Hans Rudolph, Shawnee, KS). Mixed-diluted expired O 2 (FEO 2 ) and CO 2 fractions (FECO 2 ) were measured continuously using O 2 (Oxystar-100, CWE, Inc. Ardmore, PA) and CO 2 (Model 17630, VacuMed, Ventura, CA) analyzers, as previously described (23, 24)…”

“…Oxygen uptake (V̇O 2 ) was computed as previously described (23, 25). Left ventricular systolic pressure (LVSP) and heart rate (HR) were determined and dP/dt max was analyzed by derivative of the left ventricular pressure signal.…”

Environmental toxicology of hydrogen sulfide

“…These recent observations regarding dimethylsufide generation in humans echo the earlier literature in which the “methylation pathway” was generally recognized as a detoxification route, albeit subordinate to the sulfide oxidase system [86, 144]. Finally, it appears that sulfide (H 2 S/HS − ) can only be detected in the bloodstream of both rats and sheep for a matter of seconds when administered intravenously at sub-lethal, but measurably toxic, levels [145–148]. In short, there are almost certainly multiple pathways through which sulfide can be eliminated from mammals, though these remain poorly delineated at this time.…”

“…As molecular H 2 S can freely diffuse through membranes, it readily crosses the blood-brain barrier to inhibit mitochondrial ETSs within the central nervous system. In unanesthetized laboratory animals, this results in clear behavioral signs of intoxication 2 min post-injection and can lead to death from respiratory paralysis within ~3 min [23, 97], or cardiac failure after ~7 min [147, 148]. At this time, it is not clear how to reconcile the observation that free H 2 S/HS − seemingly only persists for a matter of seconds in the bloodstream [145–148] yet onset of symptoms associated with complex IV inhibition by H 2 S/HS − begins at 2 min after the toxicant dose.…”

“…In unanesthetized laboratory animals, this results in clear behavioral signs of intoxication 2 min post-injection and can lead to death from respiratory paralysis within ~3 min [23, 97], or cardiac failure after ~7 min [147, 148]. At this time, it is not clear how to reconcile the observation that free H 2 S/HS − seemingly only persists for a matter of seconds in the bloodstream [145–148] yet onset of symptoms associated with complex IV inhibition by H 2 S/HS − begins at 2 min after the toxicant dose. We remind the reader at this point that significant numbers of human victims of H 2 S inhalation arrive at the clinic with cardiopulmonary symptoms 30 min or more after exposure and frequently succumb hours later [51, 94, 112, 154].…”