Affiliations: [a] Departments of Anesthesiology, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS, Canada
| [b] Departments of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| [c] Department of General Surgery, Dalhousie University, Halifax, NS, Canada
| [d] Department of Pharmacology, Dalhousie University, Halifax, NS, Canada
Correspondence:
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Corresponding author: Dr. Ch. Lehmann, MD, PhD, FRCPC, Sir Charles Tupper Medical Building, Room 6H, 5850 College Street, Halifax, NS, B3H 1X5 Canada. Tel.: +1 902 494 1287; E-mail: chlehmann@dal.ca.
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 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 < 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 mm/cm2, p < 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.
Keywords: Tetrahydrobiopterin, endotoxemia, peritonitis, sepsis, microcirculation, rat
