title: Absence of hydrogen sulfide-induced hypometabolism in pigs: a mechanistic explanation in relation to small nonhibernating mammals.
abstract: Artificially induced hypometabolism in nonhibernating mammals may have considerable clinical implications. Numerous studies in small rodent models have demonstrated that hydrogen sulfide (H2S) induces hypometabolism, supposedly as a result of histotoxic hypoxia. However, the induction of hypometabolism is absent in large animals following H2S administration. To determine the cause of this animal size-dependent discrepancy in H2S pharmacodynamics, the effects of sodium H2S (NaSH; 5 mg/kg/h, 4-hour intravenous administration) on systemic, pneumocardial, hematological, biochemical, microvascular (sublingual), and histological parameters were investigated in pigs. After 4 h, no differences were observed between the NaSH and control group with respect to systemic, pneumocardial, hematological, biochemical, and histological parameters. However, NaSH triggered significant hyperperfusion in the sublingual microcirculation, as evidenced by an increased blood vessel diameter (154 ± 16 and 85 ± 25% vs. baseline for NaSH and NaCl, respectively), total vessel density (139 ± 18 and 98 ± 13%, respectively), and perfused vessel density (139 ± 18 and 99 ± 13%, respectively). These phenomena are consistent with microvascular changes that occur during a panting response, an important heat loss mechanism (i.e., thermoregulatory effector) in pigs that is controlled by the thermoneutral zone (Ztn). On the basis of our findings and the literature, a mechanistic explanation is provided for the differential manifestation of hypometabolism between small and large animals. In large animals, H2S does not act via histotoxic hypoxia but likely triggers carotid bodies to transmit a hypoxic signal, which subsequently lowers the Ztn and activates heat loss mechanisms (e.g., panting) to align ATP consumption with ATP production through hypothermia. Since large animals have a small surface:size ratio, the cooling rate is too inefficient to accommodate hypothermia and subsequent hypometabolism. This is why large animals do not exhibit hypometabolism, despite the activation of thermoregulatory effectors. This is also a reason for the poor translatability of artificial hypometabolism to the clinical setting.
authors: Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Marcel C
authors: MC
authors: Dirkes
authors: Dan M J
authors: DM
authors: Milstein
authors: Michal
authors: M
authors: Heger
authors: Thomas M
authors: TM
authors: van Gulik
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D008660:Metabolism / Q000187:drug effects*; D012119:Respiration / Q000187:drug effects*; D013552:Swine
chemical_list: D006862:Hydrogen Sulfide