INFLUENCE OF GAMMA-HYDROXYBUTYRATE (GHB) ON PROINFLAMMATORY CYTOKINE GENE-EXPRESSION IN SURGICAL CORONARY PROCEDURES

Objective: To determine the influence of gamma-hydroxy-butyrate (GHB) on spontaneous and lipopolysaccharide (LPS)-stimulated release of tumo ur necrosis factor-alpha (TNF),interleukin-1 beta (IL-1 beta), interle ukin-6 (IL-6) and interleukin-10 (IL-10) in whole blood from patients undergoing coronary artery bypass grafting (CABG) with extracorporeal circulation (ECC). In addition,the pharmacological modulation on lipop olysaccharide (LPS)-stimulated cytokine release by GHB (GHB-Na and GHB -ethanolamide) was characterized in a separate in vitro-assay. Methods : In a prospective, randomized, double-blinded study, 12 patients unde rgoing elective CABG were assigned to receive either saline (control) or GHB-Na (25 mg/kg as loading dose followed by 25 mg/kg/h) intraopera tively. Blood samples were obtained (A) preoperatively,(B) 20 min afte r ECC and (C) 24 h after ECC. Plasma levels (spontaneous release) as w ell as LPS-stimulated cytokine secretion were measured in a whole bloo d culture system ex vivo and correlated with mRNA-expression in periph eral blood mononuclear cells (PBMC) In addition,the dose-response char acteristics of modulation of the cytokine response by GHB was studied in vitro in the same assay. Results: Plasma IL-6 and IL-10 levels were significantly elevated after CABG, while TNF and II-lp were detectabl e only occasionally in both groups. Expression of all cytokines studie d was significantly reduced upon ex vivo LPS-stimulation at time point B. Despite maintained expression of TNF and IL-1 beta mRNA-transcript s upon ex vivo LPS-stimulation in patients treated with GHB, release o f the cytokines in the supernatant was decreased to a similar degree a s in the control group. Cytokine response upon LPS-stimulation was res tored 24 h after CABG for the group mean, however, with substantial in dividual heterogenity. In vitro, pharmacological doses of GHB-Na (2 mg /ml) attenuated LPS-induced IL-1 beta release. However,application of the GHB-receptor antagonist NCS-382 caused a nearly complete cessation of IL-1 beta release in vitro (to 2,5% of control). GHB-ethanolamide (IK 544) did not influence the LPS-stimulated release of the cytokines studied. Conclusion: The results suggest a biphasic response of stimu lated PBMC cytokine gene expression during CABG with an initial tolera nce to IFS-stimulation shortly after termination of ECC. However,wheth er or not PBMC express functional GHB receptors remains unclear in lig ht of contradictory effects of the different ligands. In spite of the exvivo and in vitro results, application of GHB-Na in doses which are primarily based on its use as an anesthetic agent do not seem to modul ate the release of the cytokines studied.