title: Lysozyme, a mediator of sepsis that produces vasodilation by hydrogen peroxide signaling in an arterial preparation.
abstract: In septic shock, systemic vasodilation and myocardial depression contribute to the systemic hypotension observed. Both components can be attributed to the effects of mediators that are released as part of the inflammatory response. We previously found that lysozyme (Lzm-S), released from leukocytes, contributed to the myocardial depression that develops in a canine model of septic shock. Lzm-S binds to the endocardial endothelium, resulting in the production of nitric oxide (NO), which, in turn, activates the myocardial soluble guanylate cyclase (sGC) pathway. In the present study, we determined whether Lzm-S might also play a role in the systemic vasodilation that occurs in septic shock. In a phenylephrine-contracted canine carotid artery ring preparation, we found that both canine and human Lzm-S, at concentrations similar to those found in sepsis, produced vasorelaxation. This decrease in force could not be prevented by inhibitors of NO synthase, prostaglandin synthesis, or potassium channel inhibitors and was not dependent on the presence of the vascular endothelium. However, inhibitors of the sGC pathway prevented the vasodilatory activity of Lzm-S. In addition, Aspergillus niger catalase, which breaks down H(2)O(2), as well as hydroxyl radical scavengers, which included hydroquinone and mannitol, prevented the effect of Lzm-S. Electrochemical sensors corroborated that Lzm-S caused H(2)O(2) release from the carotid artery preparation. In conclusion, these results support the notion that when Lzm-S interacts with the arterial vasculature, this interaction results in the formation of H(2)O(2), which, in turn, activates the sGC pathway to cause relaxation. Lzm-S may contribute to the vasodilation that occurs in septic shock.
authors.affiliation: Health Sciences Centre, Winnipeg, Manitoba, Canada R3A 1R9. minksn@cc.umanitoba.ca
authors.forename: Steven N
authors.initials: SN
authors.lastname: Mink
authors.forename: Krika
authors.initials: K
authors.lastname: Kasian
authors.forename: Luis E
authors.initials: LE
authors.lastname: Santos Martinez
authors.forename: Hans
authors.initials: H
authors.lastname: Jacobs
authors.forename: Ratna
authors.initials: R
authors.lastname: Bose
authors.forename: Zhao-Qin
authors.initials: ZQ
authors.lastname: Cheng
authors.forename: R Bruce
authors.initials: RB
authors.lastname: Light
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D002343:Carotid Artery, Internal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006873:Hydroquinones / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008353:Mannitol / Q000494:pharmacology; D017538:Mesenteric Artery, Superior / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008751:Methylene Blue / Q000494:pharmacology; D009113:Muramidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D000071756:Soluble Guanylyl Cyclase; D013873:Thionucleotides / Q000494:pharmacology; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000634:Aminoquinolines; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D006873:Hydroquinones; D010069:Oxadiazoles; D011453:Prostaglandins; D047428:Protein Kinase Inhibitors; D011810:Quinoxalines; D018160:Receptors, Cytoplasmic and Nuclear; D013873:Thionucleotides; D014662:Vasoconstrictor Agents; C098740:8-bromo-beta-phenyl-1,N(2)-ethenoguanosine 3',5'-cyclic monophosphorothioate; D010656:Phenylephrine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D000431:Ethanol; D008353:Mannitol; C041715:6-anilino-5,8-quinolinedione; D006861:Hydrogen Peroxide; D002374:Catalase; D019001:Nitric Oxide Synthase; D017869:Cyclic GMP-Dependent Protein Kinases; D009113:Muramidase; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; D008751:Methylene Blue; C031927:hydroquinone; D007213:Indomethacin