Sulfide Toxicity and Its Modulation by Nitric Oxide in Bovine Pulmonary Artery Endothelial Cells

Abstract

Bovine pulmonary artery endothelial cells (BPAEC) respond in a dose-dependent manner to millimolar (0-10) levels of sodium sulfide (NaHS). No measurable increase in caspase-3 activity and no change in the extent of autophagy (or mitophagy) were observed in BPAEC. However, lactate dehydrogenase levels increased in the BPAEC exposed NaHS, which indicated necrotic cell death. In the case of galactose-conditioned BPAEC, the toxicity of NaHS was increased by 30% compared to that observed in BPAEC maintained in the regular glucose-containing culture medium, which indicated a link between mitochondrial oxidative phosphorylation and the mechanism of toxicant action. This is consistent with the widely held view that cytochrome c oxidase (complex IV of the mitochondrial electron-transport system) is the principal molecular target involved in the acute toxicity of "sulfide" (HS/HS). In support of this view, elevated NO (which can reverse cytochrome c oxidase inhibition) ameliorated the toxicity of NaHS and, conversely, suppression of endogenous NO production exacerbated the observed toxicity. Respirometric measurements showed the BPAEC to possess a robust sulfide oxidizing system, which was able to out-compete cytochrome c oxidase for available HS/HS at micromolar concentrations. This detoxification system has previously been reported by other groups in several cell types, but notably, not neurons. The findings appear to provide some insight into the question of why human survivors of HS inhalation frequently present at the clinic with respiratory insufficiency/pulmonary edema, while acutely poisoned laboratory animals tend to either succumb to cardiopulmonary paralysis or fully recover without any intervention.

A Comparison of Potential Azide Antidotes in a Mouse Model

“…Sulfide poisoning in mice, however, requires ∼300 μmol/kg vs 100 μmol/kg cyanide. In the case of sulfide, there are sulfide oxidizing units in a number of cell types − and potentially many more targets, as sulfide is a good reductant and quite reactive with a variety of biomolecules. The speed with which cyanide (and sulfide) reacts may also be due to the fact that much of the administered cyanide (and sulfide) is present in the body as the un-ionized molecular acid.…”

Antidotal Action of Some Gold(I) Complexes toward Phosphine Toxicity

“…An Oxygraph O2k Polarographic instrument (Oroboros Instruments, Innsbruck, Austria), equipped with a Clark-type electrode for high-resolution respirometry, was used to measure oxygen flux. Mitochondrial buffer, MiR05, 27 (2.1 mL) was added to both chambers of the respirometer and allowed to equilibrate for 20 min at 25 °C before ∼100 μL of the mitochondrial particles (prepared as above) was added. Mitochondrial respiration was then observed with the addition of cytochrome c (final concentration 10 μM), succinate (final concentration 10 mM), and rotenone (to prevent back reaction through complex I, final concentration 0.5 μM).…”