Hydrogen sulfide as a cryogenic mediator of hypoxia-induced anapyrexia

Hypoxia causes a regulated decrease in body temperature (Tb), a response that has been aptly called anapyrexia, but the mechanisms involved are not completely understood. The roles played by nitric oxide (NO) and other neurotransmitters have been documented during hypoxia-induced anapyrexia, but no information exists with respect to hydrogen sulfide (H2S), a gaseous molecule endogenously produced by cystathionine β-synthase (CBS). We tested the hypothesis that H2S production is enhanced during hypoxia and that the gas acts in the anteroventral preoptic region (AVPO; the most important thermosensitive and thermointegrative region of the CNS) modulating hypoxia-induced anapyrexia. Thus, we assessed CBS and nitric oxide synthase (NOS) activities [by means of H2S and nitrite/nitrate (NOx) production, respectively] as well as cyclic adenosine 3′,5′-monophosphate (cAMP) and cyclic guanosine 3′,5′-monophosphate (cGMP) levels in the anteroventral third ventricle region (AV3V; where the AVPO is located) during normoxia and hypoxia. Furthermore, we evaluated the effects of pharmacological modifiers of the H2S pathway given i.c.v. or intra-AVPO. I.c.v. or intra-AVPO microinjection of CBS inhibitor caused no change in Tb under normoxia but significantly attenuated hypoxia-induced anapyrexia. During hypoxia there were concurrent increases in H2S production, which could be prevented by CBS inhibitor, indicating the endogenous source of the gas. cAMP concentration, but not cGMP and NOx, correlated with CBS activity. CBS inhibition increased NOS activity, whereas H2S donor decreased NOx production. In conclusion, hypoxia activates H2S endogenous production through the CBS-H2S pathway in the AVPO, having a cryogenic effect. Moreover, the present data are consistent with the notion that the two gaseous molecules, H2S and NO, play a key role in mediating the drop in Tb caused by hypoxia and that a fine-balanced interplay between NOS-NO and CBS-H2S pathways takes place in the AVPO of rats exposed to hypoxia.

▶Anapyrexia induced by hypoxia is potentiated by hydrogen sulphide. ▶Hydrogen sulfide production is enhanced in the preoptic area during hypoxia. ▶Preoptic nitric oxide synthesis is downregulated by hydrogen sulfide.