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ANESTHETIC PHARMACOLOGY

Thiopental Inhibits Lipopolysaccharide-Induced Tissue Factor Expression

Matthias Hartmann, Priv Doz Dr med^*, Semih Özlügedik, Dr med, and Juergen Peters, Prof Dr med^*

From the *Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen, Universitätsklinikum Essen, Essen, Germany; and Klinik für Anästhesiologie, Universität Düsseldorf, Universitätsklinikum Düsseldorf, Düsseldorf, Germany.

Address correspondence to Hartmann M, Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen, Hufelandstr. 55, D-45122 Essen, Germany. Address e-mail to matthias.hartmann{at}uni-due.de.

BACKGROUND: During Gram-negative sepsis, lipopolysaccharide (LPS) stimulates toll-like receptor 4, resulting in an activation of the immune system and the expression of tissue factor on monocytes. As a consequence, intravascular coagulation, ischemia, and multiorgan dysfunction may occur. Because thiopental has been described to modulate the immune system, we tested the hypothesis that thiopental alters the LPS-induced tissue factor expression.

METHODS: (i) Citrated whole blood samples were incubated with thiopental (0, 0.25, 0.5, 1 mg/mL) and LPS (100 µg/mL) for 4 h. After recalcification, clotting time (CT) was determined by rotational thrombelastometry. (ii) The mechanism of the LPS-induced shortening of CT was investigated using the tissue factor blocker active-site inhibited factor VIIa and the protein synthesis inhibitor cycloheximide. (iii) A concentration response curve for the effect of tissue factor on CT was generated.

RESULTS: LPS shortened CT from 618 ± 122 s to 192 ± 33 s (n = 6; P < 0.05). Shortening of CT was mediated by synthesis of tissue factor, because both inhibition of protein synthesis and blockade of tissue factor effects abolished this effect of LPS. Thiopental markedly inhibited the LPS-induced shortening of CT (372 ± 86 s; n = 6; P < 0.001). Comparison of CT with a tissue factor standard curve demonstrated that thiopental reduced the LPS-induced tissue factor activity up to 86%. A direct effect of thiopental on coagulation was excluded, because tissue factor-induced CT was not affected by the barbiturate.

CONCLUSIONS: Thiopental markedly inhibits the LPS-induced tissue factor expression in whole blood samples.