angiotensin-iii and Shock--Septic

C1-Inhibitor (Berinert, C1 INH), a 104 kDa protein, inhibits complement components (C1 esterase) as well as enzymes of the contact phase of coagulation (Factor XII, Factor XI) and kallikrein, thus regulating kinin generation. C1 INH is used for the treatment of the hereditary angioneurotic edema. This paper will give a survey about the evidence in recent literature concerning the potential efficacy of the compound on other diseases associated with shock, capillary leakage and inflammation as well. In our own experiments we evaluated whether the compound could influence acute inflammatory reactions or the severe systemic inflammatory response syndrome (SIRS) as a consequence of an experimental septic shock. To prevent the sepsis-induced DIC we co-infused the thrombin inhibitors AT III or rec. hirudin in combination with C1 INH. Coinfusion of C1-inhibitor (50-200 U/kg x h) with either rec. hirudin or AT III significantly improved survival rate compared to thrombin inhibitor alone.

Topics: Angioedema; Angiotensin III; Animals; Complement C1 Inactivator Proteins; Disseminated Intravascular Coagulation; Edema; Female; Hirudin Therapy; Humans; Inflammation; Lipopolysaccharides; Rats; Rats, Inbred Lew; Shock, Septic; Survival Rate

We have examined the effects of an inhibitor of plasminogen activator inhibitor-1 (PAI-1) production, (3E,4E)-3-benzylidene-4-(3,4,5-trimethoxy-benzylidene)pyrrol idine-2,5-dione (T-686), on lipopolysaccharide (LPS)-induced death in mice. Oral administration of T-686 (10 and 100 mg/kg/day) for 8 days prior to the LPS injection (35 mg/kg, i.v.) protected mice from the lethal effect of LPS in a dose-dependent fashion. Moreover, treatment with 100 mg/kg T-686 attenuated the increase in plasma PAI-1 activity and the decrease in AT-III activity induced by LPS. We conclude that T-686 can reduce the mortality of mice induced by LPS, which seems to be partially correlated with both hypercoagulation and hypofibrinolysis.

Topics: Angiotensin III; Animals; Anticoagulants; Benzylidene Compounds; Blood Coagulation; Dose-Response Relationship, Drug; Endotoxins; Fibrinolysis; Heparin; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Plasminogen Activator Inhibitor 1; Shock, Septic; Succinimides; Survival Rate

Levels of components of the contact activation, coagulation, and complement systems and their main inhibitors were measured in 45 critically ill patients during 61 episodes of uncomplicated bacteremia or bacterial shock. Levels of Hageman factor (factor XII), prekallikrein, high-molecular-weight kininogen, factor XI, factor VII, total hemolytic complement, alternative pathway activity, and C3 were within the normal range during uncomplicated bacteremia (n = 29), but during fatal bacterial shock (n = 13) a significant decrease by 40%-50% was observed in all measurements. During nonfatal bacterial shock (n = 19) a moderate decrease was observed in most of these measurements. The capacity of plasma to inactivate kallikrein was significantly higher during bacteremia than during bacterial shock because of a significant increase in the level of C1 esterase inhibitor. Levels of antithrombin III and alpha 2-macroglobulin were below normal in all groups. Thus increased inhibition of the contact activation and complement systems is beneficial during bacteremia.

Topics: alpha-Macroglobulins; Angiotensin III; Blood Coagulation; Complement Activation; Complement C1 Inactivator Proteins; Complement C3; Factor VII; Factor XI; Factor XII; Humans; Kininogens; Prekallikrein; Sepsis; Shock, Septic