Lysozyme, a mediator of sepsis that produces vasodilation by hydrogen peroxide signaling in an arterial preparation

Departments of 1 Medicine, 2 Pharmacology and Therapeutics, and 3 Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and 4 Instituto Nacional de Cardiologia Ignacio Chavez, Mexico City, Mexico Submitted 15 September 2007 ; accepted in final form 6 February 2008 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. reactive oxygen species; catalase; compound I; hydroxyl radical; septic shock; hypotension Address for reprint requests and other correspondence: S. N. Mink, Health Sciences Centre, GF-221, 820 Sherbrook St., Winnipeg, Manitoba, Canada R3A 1R9 (e-mail: minksn{at}cc.umanitoba.ca )