N,N',N"-triacetylglucosamine, an inhibitor of lysozyme, prevents myocardial depression in Escherichia coli sepsis in dogs.
OBJECTIVE
Reversible myocardial depression in sepsis has been ascribed to the release of inflammatory mediators. We recently found that lysozyme c (Lzm-S), consistent with that originating from the spleen, was a mediator of myocardial depression in an Escherichia coli model of septic shock in dogs. We further showed in a right ventricular trabecular (RVT) preparation that Lzm-S's depressant activity could be blocked by N,N',N" triacetylglucosamine (TAC), a competitive inhibitor of Lzm-S. We hypothesized that Lzm-S binds to or cleaves a cardiac membrane glycoprotein, thereby interfering with myocardial contraction in sepsis. In the present study, we examined whether TAC could prevent myocardial depression in an in vivo preparation and whether other related N-acetylglucosamine (NAG) structures could also inhibit Lzm-S's effect in RVT.


METHODS
Randomized experimental study.


METHODS
University laboratory.


METHODS
Anesthetized, mechanically ventilated dogs.


METHODS
We produced sepsis by infusion of E. coli over an approximately 6-hr period.


RESULTS
We examined the effect of TAC on stroke work, our primary index of myocardial function, when treatment was administered before sepsis (pretreatment) and after 1.5 hrs (early treatment study) and 3.5 hrs of sepsis (late treatment study; LTS). In the pretreatment study and early treatment study, myocardial depression would have not yet occurred but would have already been present in the late treatment study. In RVT, we assessed the effect of other NAG oligosaccharides and variants to the NAG structure on Lzm-S's depressant activity. In pretreatment and the early treatment study, TAC prevented the reduction in stroke work observed in nontreated septic groups but did not reverse the reduction found in the late treatment study. In RVT, of the compounds tested, only N,N'-diacetylglucosamine showed an inhibitory effect.


CONCLUSIONS
We found that TAC, a competitive inhibitor of Lzm-S, prevented myocardial depression in experimental sepsis. Only specific NAG structures are inhibitory to Lzm-S's depressant activity. TAC may be useful in attenuating cardiovascular collapse in sepsis.
Mink
Steven N
SN
Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg. minksn@cc.umanitoba.ca
Jacobs
Hans
H
Duke
Krika
K
Bose
Deepak
D
Cheng
Zhao-Qin
ZQ
Light
R Bruce
RB
D000118:Acetylglucosaminidase / Q000494:pharmacology*; D000818:Animals; D002302:Cardiac Output / Q000187:drug effects*; D004195:Disease Models, Animal; D004285:Dogs; D004927:Escherichia coli Infections / Q000188:drug therapy*; D005260:Female; D008297:Male; D009113:Muramidase / Q000187:drug effects / Q000378:metabolism*; D009200:Myocardial Contraction / Q000187:drug effects; D009201:Myocardial Depressant Factor / Q000032:analysis; D011336:Probability; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity; D012772:Shock, Septic / Q000188:drug therapy*; D013318:Stroke Volume / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000517:prevention & control*
D009201:Myocardial Depressant Factor; D009113:Muramidase; D000118:Acetylglucosaminidase