Effects of Hydrogen Sulfide in Vertebrate Smooth Muscle

Hydrogen sulfide (H2S) is an endogenously produced gas affecting the mammalian nervous system and smooth muscle (SM). While mechanisms of H2S action have been proposed, these models require further testing and the biological role of H2S within the vasculature remains to be elucidated. The present study utilized plasma [H2S] measurement, enzymatic H2S production assays, and SM myography to examine the evolution of H2S as a gasotransmitter and to determine its mechanism of action and physiological role in select vertebrate SM. This study found H2S vasoactivity in all vertebrate classes ranging from mono-phasic relaxation and contraction to complex multi-phasic responses. Various phases of the muli-phasic relaxation-contraction-relaxation response in trout vessels were sensitive to KATP/Cl- channel inhibition, endothelial modification, and pH manipulation, but independent of [cGMP] and extracellular [Ca2+]. Trout plasma [H2S] was ~40 ÌÂM, near effective dilatory concentrations of pre-contracted trout vessels (EC50 67 å± 9 ÌÂM). H2S-induced relaxation of trout urinary bladder was insentive to most manipulations with the exception of KCl prestimulus. Removal of extracellular chloride (0 [Cl-]o) and blocking Cl- channels altered the mechanical responses of lamprey, trout, and rat vessels to H2S. Changes in Po2 elicit a variety of responses in SM to match physiological requirements. The mechanisms by which SM cells sense Po2 are heavily debated. The redox relationship between H2S and O2 suggests H2S could serve as an O2 sensing molecule in SM. These studies found; (1) hypoxia and H2S produce temporally and quantitatively identical responses; (2) responses to hypoxia and H2S are mutually exclusive, the presence of one stimulus, substantially or completely eliminates the response to the other; (3) H2S is synthesized by SM; (4) increasing [substrate] for H2S production increases vessel response to hypoxia; and (5) inhibition of H2S synthesis inhibits responses to hypoxia. In addition, manipulation of [Cl-]o and inhibitors of Cl- trafficking had similar effects on responses to H2S and hypoxia. H2S is a phylogenetically ancient and versatile regulatory molecule appearing to be opportunistically suited to meet organ- and species-specific homeostatic requirements. H2S appears to act through a Cl- sensitive pathway and is intrinsically coupled to cellular O2 sensing.