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H2S Induces a Suspended Animation–Like State in Mice

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Science  22 Apr 2005:
Vol. 308, Issue 5721, pp. 518
DOI: 10.1126/science.1108581

Abstract

Mammals normally maintain their core body temperature (CBT) despite changes in environmental temperature. Exceptions to this norm include suspended animation–like states such as hibernation, torpor, and estivation. These states are all characterized by marked decreases in metabolic rate, followed by a loss of homeothermic control in which the animal's CBT approaches that of the environment. We report that hydrogen sulfide can induce a suspended animation-like state in a nonhibernating species, the house mouse (Mus musculus). This state is readily reversible and does not appear to harm the animal. This suggests the possibility of inducing suspended animation-like states for medical applications.

Many organisms respond to changes in environmental conditions by entering into a suspended animation–like state in which a decrease in metabolic rate (MR) is followed by a reduction in core body temperature (CBT) (1). Regulated induction of a hypometabolic state is hypothesized to have great medical benefit for a variety of conditions, including ischemia and reperfusion injury, pyrexia, and other trauma (2). Suspended animation–like states may also be useful for creating beneficial hypothermia in surgical situations and for improving organ preservation (1).

Inhibiting oxidative phosphorylation reversibly induces states of profound hypometabolism in several model organisms (35). Because hydrogen sulfide (H2S) is a specific, potent, and reversible inhibitor of complex IV (cytochrome c oxidase), the terminal enzyme complex in the electron transport chain (6), we hypothesized that it could reduce MR and CBT in mammals.

When mice were exposed to 80 ppm of H2S, their oxygen (O2) consumption dropped by ∼50% and their carbon dioxide (CO2) output dropped by ∼60% within the first 5 minutes (Fig. 1A) (7). If left in this environment for 6 hours, their MR dropped by ∼90% (Fig. 1A). The MR of control mice, as judged from O2 consumption and CO2 output increases (8). This drop in MR was followed by a drop in CBT to ∼2°C above ambient temperature (Fig. 1B). The average CBT of these mice reached a minimum of 15°C in an ambient temperature of 13°C (Fig. 1B). At this minimum CBT, both CO2 output and O2 consumption was ∼10% of normal (Fig. 1A), and the breathing rate of the mice decreased from ∼120 breaths per minute (BPM) to less than 10 BPM (8). After 6 hours of exposure to H2S, the mice were returned to room air and temperature, and their MR and CBT returned to normal (Fig. 1, A and B).

Fig. 1.

CBT and MR of mice exposed to H2S. (A) Relative CO2 production and O2 consumption of mice exposed to 80 ppm of H2S. (B) CBT of mice during 6 hours of exposure to either 80 ppm of H2S (black line) or the control atmosphere (gray line). The dotted line indicates ambient temperature. Values in (A) and (B) are means ± one standard deviation. (C) Linear relationship between H2S concentration and CBT (R2 = 0.95) after 6 hours of exposure. (D) CO2 output and CBT of mice (time = 0 at the start of H2S exposure).

Exposing mice to varying concentrations of H2S revealed a linear relationship between the concentration of H2S and CBT (Fig. 1C). CBT dropped faster and reached lower temperatures as concentrations of H2S increased from 0 to 80 ppm (8), suggesting that the effects of H2S are concentration-dependent. However, this MR reduction is not dependent on ambient temperature (fig. S1).

Because H2S can be toxic in high doses, we conducted behavioral and functional tests, selected from the SHIRPA protocol (9), to assay for H2S-induced damage. No behavioral or functional differences in the mice were detected after exposure to 80 ppm of H2S for 6 hours (8). In the absence of H2S, no effect on CBT was observed (Fig. 1B, control atmosphere). In addition, others report no long-term health effects with these H2S concentrations (6).

The sequential drop in MR and CBT observed in mice (Fig. 1D) exposed to 80 ppm of H2S is similar to that observed when animals initiate hibernation, daily torpor, or estivation (1). On-demand induction of a suspended animation–like state could provide insight into the mechanisms that govern natural states of reduced metabolism. Lowering metabolic demand in this way could be used to reduce physiological damage resulting from trauma and might improve outcomes after surgery.

Supporting Online Material

www.sciencemag.org/cgi/content/full/308/5721/518/DC1

Materials and Methods

SOM Text

Fig. S1

References and Notes

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