Significant progress has been made in determining the action of sulfide on the primary target organs. It is reasonably clear that sulfide causes both K(+)-channel-mediated hyperpolarization of neurons and potentiation of other inhibitory mechanisms. It is not clear whether these processes are similar to those that occur in anoxia. Changes in perinatal and adult brain neurotransmitter content and release may be related to clinical impairment of cognition. H2S exposures at concentrations below the current occupational limits cause physiological changes in pulmonary function, thus suggesting that asthmatics are at risk. Studies of fetal and neonatal brain tissue have shown an abnormal development, and the long-term consequences of these neuronal changes have not yet been assessed. Finally, new approaches to therapy are required, such as the use of agents that actively remove sulfide from its sites of action. This may prove more useful in preventing some of the long-term adverse sequelae than the use of nitrites and hyperbaric O2, although the latter should be used in cases of pulmonary edema.

An analytical method for the determination of sulfide in human and rat brain is described. It utilizes a continuous flow gas dialysis pretreatment and quantitation by ion chromatography with electrochemical detection. Rat brain sulfide levels were reliably measured after fatal intoxication by intraperitoneal injection of NaHS. By expeditious analysis of samples it was possible to demonstrate the presence of endogenous levels of sulfide in both rat and human brain as well as to measure elevated brain levels of sulfide after intoxication. In postmortem rat brain tissue, elevated sulfide levels could still be reliably demonstrated 96 h after death if the bodies had been refrigerated at 4 degrees C. Two case studies of human hydrogen sulfide inhalation fatalities are presented. The described method was able to measure significantly elevated sulfide levels in both cases.

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In rats under urethane anaesthesia, changes in the extracellular activities of K+ and Ca2+ (alpha K and alpha Ca) evoked by fimbrial or entorhinal stimulation and recorded in area CA3 with ion-selective microelectrodes are maximal in the pyramidal cell layers. With 10/s stimulation, alpha K increases by 6--9 mM whereas alpha Ca falls by 0.5--1.0 mM. In contrast with the increase in alpha K, which is distributed over a wide range of depth, the reduction in alpha Ca is particularly sharply limited to the level of pyramidal cell bodies. It is regularly associated with a negative aferpotential in the extracellular field, which presumably reflects a large postsynaptic Ca2+ inward current, apparently predominant in the cell bodies. Repetitive stimulation sometimes evokes spreading depressionlike swings in potential, which are seen only near the pyramidal stratum and are accompanied by massive increases in alpha K (to 30--40 mM) and falls in alpha Ca (to < 0.1 mM). A large Ca2+ influx into pyramidal cells may be of significance for "plastic" aspects of hippocampal function and when excessive, as during repetitive convulsive activity, may be responsible for the necrosis of CA3 neurons.

Abstract. Acid-labile sulfide measured by conventional gas dialysis and ion chromatography with electrochemical detection accounts for only a proportion of the total sulfide present in brain tissue after poisoning with NariS, an H2S precursor. Dithiothreitol (DTT) displaced additional measurable sulfide not detectable by the conventional techniques from NariS-poisoned brain tissue. Sulfide liberation by DTT was dose-dependent and maximal at higher DTI" concentration (10 and 30 mM) and was thought to represent non-acid labile sulfide. Dithiothreitol was also found to be significantly protective against H2S poisoning. Furthermore, in vitro inhibition by sulfide of monoamine oxidase (MAO) was reversed by DTT, thus suggesting a molecular mechanism consistent with known persulfide chemistry. Persulfide formation may thus underlie some aspects of hydrogen sulfide neurotoxicity. The rational development of antidotes for use in H2S poisoning may thus have to be centered on strategies concentrating on known thiol, disulfide and persulfide chemistry.

In urethane-anaesthetized rats, ion-selective microelectrodes recorded changes in extracellular K+ and Ca2+ concentrations (delta[K+]omicron and delta[Ca2+]omicron) in pyramidal layers of the hippocampus (mostly in area CA1), which were evoked by fimbrial-commissural stimulation. [K+]omicron increased linearly with frequency of stimulation up to a critical frequency, in the range of 2-5 Hz, where bursts of population spikes appeared, and then rose rapidly to reach a ceiling of 9-12 mM. During continued stimulation, [K+]omicron remained well above the resting level of about 3.0 mM. At the end of stimulation [K+]omicron returned to the base line with a half time of 4-8 s, and a minor undershoot of congruent to 0.5 mM was detectable for 1-2 min. When stimulating at frequencies above the critical value, a sharp fall in [Ca2+]omicron (by an average of one-third below the mean resting level of 1.4 mM) consistently started 1-5 s after the onset of the rapid phase of delta[K+]omicron. [Ca2+]omicron typically reached a minimum in 5-10 s and immediately started to return towards the base line. The recovery of [Ca2+]omicron was often accelerated by an overshoot of up to 0.3 mM; this was followed by a delayed phase of low [Ca2+]omicron for another 2-3 min. During prolonged stimulation at frequencies near 7 Hz, both [Ca2+]omicron and [K+]omicron fluctuated periodically, in time with the appearance and disappearance of bursts of population spikes. Comparable observations were made in area CA2-3 (just external to CA1); in the deeper areas of CA3, in CA4, and in the dentate gyrus, major changes in [K+]omicron and [Ca2+]omicron (as well as bursts of population spikes) were evoked only by prolonged fimbrial stimulation at higher frequencies (congruent to 10 Hz). Thus, although adequate repetitive stimulation of fimbrial-commissural inputs evokes sharp but opposite changes in [K+]omicron and [Ca2+]omicron, the fall in [Ca2+]omicron is consistently much briefer than the rise in [K+]omicron, presumably because of the evanescent character of postsynaptic Ca2+ spikes.

1. Hydrogen sulphide (H2S) is a broad spectrum toxicant that occurs widely in nature and is also released by a variety of industrial activities and processes. 2. The central nervous system (CNS) appears to be the major target organ. 3. There is great potential for insult or injury to the developing or immature CNS. 4. The risk of chronic or repeated exposures to low concentrations have not been well defined. 5. Exposure to low concentrations of H2S to time-pregnant rats from day 5 postcoitus until day 21 postnatal results in architectural modification of cerebellar Purkinje cells, alteration of putative amino acid neurotransmitters and changes in monoamine levels in the developing rat brain up to day 21 postnatal. 6. H2S-induced alterations in monoamine tissue levels observed in the developing rat brain return to control values if exposure is discontinued during development, that is, at day 21 postnatal.