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. DESIGN: Randomized experimental study. SETTING: University laboratory. SUBJECTS: Anesthetized, mechanically ventilated dogs. INTERVENTIONS: We produced sepsis by infusion of E. coli over an approximately 6-hr period. MEASUREMENTS AND MAIN 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.

Disfunción ventricular: el shock séptico / Ventricular dysfunction in septic shock

A pesar del uso amplio de antibióticos y manejo hemodinámico adecuado, el shock séptico ha ido aumentando de frecuencia y es fatal en aproximadamente la mitad de los pacientes. La disfunción miocárdica es una complicación común de pacientes con tensión

A study of the myocardial depressant factor and its relative influence in drug/alcohol mortality.

A shock factor, a low molecular weight peptide, has been isolated from postmortem blood. High levels of this peptide, which depresses the myocardium, were seen in cases where drug overdose or alcoholism, or both, were the cause of death. An elevated myocardial depressant factor (MDF) level also demonstrated in a fire victim and a patient in cardiogenic shock. The peptide analysis was accomplished by using an isolated cat papillary muscle followed by paper chromatographic confirmation. Postmortem electrolytes, alcohol, and various toxic agents were eliminated as causes of myocardial depression in the isolated cat papillary muscle assay. The presence of elevated MDF levels may be significant in the overall death process.

The chemical nature of a pancreatic cardiodepressant factor.

The presence of a cardiodepressant factor of pancreatic origin has been reported in the plasma of experimental animals and man in a variety of shock states. It has been suggested that the depression of developed tension of the isolated cat papillary muscle may be caused by excess NaCl in the bathing medium rather than a specific cardiodepressant peptide. Incubated pancreatic homogenate was used as a source of this factor, and after protein precipitation, ultrafiltration (10,00 and 1,000 MW), dialysis and lyophilization, the residue was applied to a Sephadex G-10 column in order to ensure the removal of all salts. The protein effluent of the Sephadex column contained all the cardiodepressant activity of the filtered, dialyzed pancreatic homogenate and none of the salt content. To further isolate this cardiodepressant factor, the active residue was applied to a cellulose column and eluted with butanol: glacial acetic acid: water (25:26 v/v/v). This elution gave 8 distinct peptide peaks, one of which, peak 4, contained significant depressant activity. Thus, a cardiodepressant peptide of approximately 250-1,000 MW exists in pancreatic homogenates and this compound is not excess NaCl in the assay system.