Einfluß von Gamma- Hydroxy-Buttersäure (GHB) auf die proinflammatorische Zytokin-Genexpression bei koronarchirurgischen Eingriffen

Objective: To determine the influence of gamma-hydroxy-butyrate (GHB) on spontaneous and lipopolysaccharide (LPS)-stimulated release of tumour necrosis factor-alpha (TNF),interleukin-1 β (IL-1β)),interleukin-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 lipopolysaccharide (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 undergoing elective CABG were assigned to receive either saline (control) or GHB-Na (25 mg/kg as loading dose followed by 25 mg/kg/h) intraoperatively. Blood samples were obtained (A) preoperatively, (B) 20 min after ECC and (C) 24 h after ECC. Plasma levels (spontaneous release) as well as LPS-stimulated cytokine secretion were measured in a whole blood culture system ex vivo and correlated with mRNA-expression in peripheral blood mononuclear cells (PBMC). In addition,the dose-response characteristics 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 IL-1β were detectable only occasionally in both groups. Expression of all cytokines studied was significantly reduced upon ex vivo LPS-stimulation at time point B. Despite maintained expression of TNF and IL-1β m-RNA-transcripts upon ex vivo LPS-stimulation in patients treated with GHB, release of the cytokines in the supernatant was decreased to a similar degree as in the control group.Cytokine response upon LPS-stimulation was restored 24 h after CABG for the group mean, however, with substantial individual heterogenity.In vitro, pharmacological doses of GHB-Na (2 mg/ml) attenuated LPS-induced IL-1β release. However, application of the GHB-receptor antagonist NCS-382 caused a nearly complete cessation of IL-1β release in vitro (to 2,5% of control). GHB-ethanolamide (LK 544) did not influence the LPS-stimulated release of the cytokines studied. Conclusion: The results suggest a biphasic response of stimulated PBMC cytokine gene expression during CABG with an initial tolerance to LPS-stimulation shortly after termination of ECC. However, whether or not PBMC express functional GHB receptors remains unclear in light of contradictory effects of the different ligands. In spite of the ex vivo and in vitro results, application of GHB-Na in doses which are primarily based on its use as an esthetic agent do not seem to modulate the release of the cytokines studied.