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In septic shock (SS), hydrogen peroxide (H2O2) and other reactive oxygen species (ROS) are released by inflammatory cells and have been implicated in tissue damage and inflammation. Recently, H2O2 has been established as an important signaling molecule and an important component of SS. The pathways involved in this process are not completely understood, but the formation of hydroperoxides (HPs), arachidonic acid (AA) metabolites and potassium (K+) channels have been implicated. In this study, we used a canine carotid ring preparation as a bioassay to determine the role of peroxyacetic acid (POX), a hydroperoxide (HP), in causing vasodilation and elucidate the subsequent pathways involved. We removed internal carotid artery segments from dogs and placed them in an organ bath. The segments were preconstricted after which we added POX to the preparation. We found that POX produced an endothelium and nitric oxide independent vasodilation in the carotid artery ring preparation. This decrease in tension could be prevented by high concentrations of K+ in the bath. This suggested that K+ channels were involved in POX’s action. Further investigation showed that the particular K+ channels implicated were the combination of small (SKCa) and intermediate conductance calcium activated K+ channels (IKCa). In addition we found that the prostaglandin H synthase (PGHS) inhibitor, indomethacin, could block POX’s mechanism of action. This finding indicates that PGHS takes part in the vasodilation caused by POX. Our results suggest that HPs that are released from inflammatory cells in sepsis could stimulate the PGHS pathway leading to prostaglandin synthesis and subsequently activating SKCa and IKCa to produce vasodilation. Inhibition of this pathway may be important component in the treatment of SS.

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Glutamate-gated chloride channels (GluCl) belong to then icotinic ligand-gated ion channel family and are thus assumed to be heteropentamers. Each subunit contains a large extracellular N-terminal domain, four transmembrane domains (TM1--TM4), and an extracellular C terminal. Caenorhabditis elegans expresses various GluCl channels formed by alpha1, alpha2, alpha3, alpha4 and beta subunits. The best understood GluCl channel is expressed in pharyngeal muscle cells where it mediates response to the M3 motor neuron. alpha2 forms this channel, probably in association with beta. The alpha2 mutant lacks M3 neurotransmission which can be rescued by pharynx-specific alpha2 expression. My results show that alpha1 and alpha3 subunits cannot substitute for alpha2. Formation of chimeric constructs of alpha1, alpha2 and alpha3 pinpoints the M1--M3 transmembrane region of alpha2 as the minimal rescuing domain. This region may therefore be important for localization or, in association with another subunit, in the formation of the active channel.

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