Tetrahydrobiopterin improves microcirculation in experimental sepsis.

Abstract

BACKGROUND: Tetrahydrobiopterin (BH4), an endogenous nucleic acid derivative, acts as an important cofactor for several enzymes found within the vascular endothelium, which is deranged in sepsis. OBJECTIVE: We hypothesized that BH4 would improve capillary density and decrease inflammation within the intestinal microcirculation of septic rats. METHODS: We conducted a randomized, controlled trial using two previously validated models of sepsis in rats: 1) A fecal peritonitis model using a stent perforating the ascending colon, and 2) An endotoxemia model using lipopolysaccharide (LPS) toxin from E. coli. Experimental groups receiving BH4 (60&#x200a;mg/kg) were compared to otherwise healthy controls and to untreated groups with sepsis-like physiology. RESULTS: BH4 decreased leukocyte-endothelial adhesion by 55% and 58% (P&#x200a;<&#x200a;0.05) in the peritonitis model and endotoxemia models, respectively. In the endotoxemia model but not the peritonitis model, BH4 improved functional capillary density in capillary beds within the intestine (141.3 vs. 106.7&#x200a;mm/cm2, p&#x200a;<&#x200a;0.05). Macrohemodynamic parameters were no different between placebo treatment and BH4-treated groups. CONCLUSIONS: This study demonstrates that BH4 improves capillary density and inflammation in two separate models of sepsis. BH4 may represent a novel adjunct in the treatment of sepsis and septic shock in clinical practice. Further dose-finding studies and clinical trials are warranted.