Is exogenous hydrogen sulfide a relevant tool to address physiological questions on hydrogen sulfide?

This review challenges the use of solutions of dissolved exogenous H₂S in the literature as a tool to determine the potential physiological functions of endogenous H₂S as well as its putative therapeutic applications.Our major point of contention is that solutions of dissolved H₂S are used in vitro at concentrations, within the high microM range, which are above the concentrations of dissolved H₂S found in blood and tissues during lethal H₂S exposure in vivo. In addition, since the levels of toxicity are extremely variable among cell types, a property that is seldom acknowledged, the physiological relevance of data obtained after local or in-vitro administrations of H₂S at concentrations of few microM is far from certain. Conversely, the rate of disappearance of the dissolved pool of H₂S in the body (being trapped or oxidized), which we found to be at least of several micromoles/kg/min, is so rapid in vivo that if relatively low quantities of H₂S, i.e. few micromoles for instance, are administered, no change in H₂S concentrations in the body is to be expected, unless toxic levels are used. Protocols looking at the effects of compounds slowly releasing H₂S must also resolve a similar conundrum, as their effects must be reconciled with the unique ability of the blood and tissues to get rid of H₂S and the steepness of the dose-toxic effects relationship.Only by developing a comprehensive framework in which H₂S metabolism and toxicity will be used as a rationale to justify any experimental approach will we be able to bring definitive evidence supporting a protective role for exogenous H₂S, if any, and its putative function as an endogenous mediator.