H2S induced hypometabolism in mice is missing in sedated sheep
Introduction
The induction of hypothermia to reduce the metabolic rate may protect organs such as brain, kidney and heart, from the effects of ischemia. Despite significant interest in the development of drugs that would mimic the effects of hypothermia for the management of coma, cardiac surgery or severe trauma, no recent significant progress has been achieved in the development of pharmacological agents capable of reducing the metabolic rate to protect highly sensitive organs (Bernard and Buist, 2003, Ramani, 2006).
In 2005, a report published in Science (Blackstone et al., 2005) proposed the use of hydrogen sulfide (H2S; 20–80 ppm) to induce a “hibernation-like state” and to reduce damages resulting from a surgical, traumatic or ischemic aggression in humans. This novel and attractive therapeutic strategy was based on the observation that in mice, inhalation of H2S decreases very rapidly, within 5 min, and by more than 50% the metabolic rate which in turn was associated with a progressive reduction in body temperature (Tb).
Although the mechanisms accounting for H2S-induced hypometabolism remain unclear, this observation raised great expectations that H2S could be used in humans. This information is now spreading not only in the scientific and medical community but also in the lay press (Rincon, 2005). However, this proposal appears to ignore a large body of evidence dealing with factors capable of inducing a metabolic depression in small mammals and as a result may underestimate the impact of H2S, which is also a highly toxic gas for humans (Beauchamp et al., 1984, Tvedt et al., 1991, Reiffenstein et al., 1992). Indeed, it blocks cytochrome C oxidase activity in the electron transport chain (Dorman et al., 2002), even at the low concentrations shown to be sufficient to acutely decrease mice metabolism (Costigan, 2003).
H2S inhalation is neither the first nor the sole pharmacological intervention that reduces metabolism (Mortola, 1993, Mortola et al., 1994, Gautier, 1996). Indeed, following the initial description by Hill (1959), moderate hypoxia, resulting from a decrease in PaO2 (Gautier, 1996), anaemia (Matsuoka et al., 1994), or following CO exposure (Gautier and Bonora, 1994), has long been shown to dramatically reduce metabolism with no accumulation of anaerobic debt in resting animals (Frappell et al., 1991). Furthermore, the hypoxic metabolic response appears to be restricted to small-sized mammals (Frappell et al., 1992, Mortola, 1993, Korducki et al., 1994).
Reducing oxygen consumption (Hill, 1959, Gautier, 1996) is one of the strategies used by small mammals with a high surface/mass ratio, to prevent the deleterious effects of hypoxia (Singer, 2004). One of the fastest components of hypoxic induced metabolic decline, which reduced within few minutes by more than half, is the dramatic drop in non-shivering (obligatory) thermogenesis. Such a rapid and efficient response is thought to rely on neural mechanisms triggered by central hypoxia, i.e. possibly originating in the subthalamic regions involved in thermal and metabolic control. It is essential to note that even though a decrease in body temperature (Tb) could per se reduce metabolism (Q10 effect), the decrease in Tb during hypoxia is primarily the consequence of the decrease in rather than the reverse (Gautier, 1996). Indeed, hypoxia induced hypometabolism occurs even when Tb is kept constant (Frappell et al., 1992, Frappell et al., 1995) (see discussion for further details).
In mammals with body weight >30 kg and thus a low , this phenomenon is virtually absent (Forster et al., 1981, Frappell et al., 1992, Korducki et al., 1994), at least in normothermia (Dempsey and Forster, 1982, Robinson and Haymes, 1990). Thus, the essential question is whether, unlike during hypoxia, large mammals are capable of decreasing their metabolic rate during H2S exposure. We therefore compared the metabolic responses of resting adult mice (0.024 kg) to that of unanaesthetized sedated adult sheep (74 kg) challenged with 30 min inhalation of 60 ppm H2S. To decipher the mechanisms controlling the metabolic depression from those related to the effects of a decrease in body temperature, we determined the kinetics of the breath-by-breath pulmonary gas exchange response to H2S in sheep at an ambient temperature of 22 °C and in mice at 23° C (instead of 13 °C in the study of Blackstone) using an open flow respiratory chamber with a very fast time constant.
Section snippets
Animals and measurements
Five adult resting mice (female, C57BL/6J, 24.05 ± 1.09 g, 30 weeks old) and five unanaesthetized sedated (ketamine 5–10 mg/kg IM) adult sheep (female, 73.8 ± 7.7 kg, 5 years old) were studied. All the experiments were performed according to the recommendations of the Council of European Communities and with the authorization from the French Ministry of Agriculture and Fisheries (authorization number 54-42).
For the mice, we used a custom-made open flow chamber. The chamber consisted of a plastic tube
Results
Baseline resting specific metabolic rate in mice averaged 68 ± 12 and 55 ± 10 ml/min/kg for and , respectively. In the sheep, averaged 5.3 ± 0.7 ml/min/kg and 4.9 ± 0.5 ml/min/kg.
As illustrated in Fig. 1, H2S inhalation in mice produced a rapid, and large drop in (−50.2 ± 6.4%, p < 0.001) and (−58.3 ± 6.6%, p < 0.001). This decrease in pulmonary gas exchange reached its nadir between 124 and 145 s after the onset of H2S inhalation. Both and remained low with a slight, but
Discussion
Consistent with the previous report of Blackstone et al. (2005) and the data presented by Volpato et al. (2006), H2S produced a severe depression in metabolism in mice. In contrast, sedated sheep were unable to reduce their resting metabolic rate during a similar exposure.
The present data allow us to clarify some of the questions raised in the introduction. First, the study of the dynamics of the gas exchange response clearly reveals that H2S depresses metabolic rate well before the occurrence
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