Clinical Hemorheology and Microcirculation 67 (2017) 15–24 DOI 10.3233/CH-160207 IOS Press 15 Tetrahydrobiopterin improves microcirculation in experimental sepsis Tristan C. Dumbarton a , Alexander Maxan b , Nizam Farah b , Nivin Sharawy a , Juan Zhou b , Jordan Nantais c and Christian Lehmann a,b,d,∗ 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 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 endo- toxemia 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/cm 2 , 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 1. Introduction One of the most significant pathophysiologic changes in the setting of sepsis is a profound micro- circulatory derangement [1–4]. The microcirculation, consisting of the small arterioles, venules and capillary beds, is critical for oxygen exchange and metabolite removal in all tissues. If the micro- circulation is poorly perfused, as in sepsis and septic shock, cellular hypoxia will ensue, eventually leading to organ dysfunction and shock. Assessment of the microcirculation is becoming an increas- ingly useful tool in diagnosis and management of many disease states, and advances in technology are making in vivo measurements more accessible [5–9]. Normal microvascular endothelial function encompasses multiple processes that help maintain homeostasis, including: i) regulating blood-cell interactions (white blood cells, platelets) [10–12], ∗ 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. 1386-0291/17/$35.00 © 2017 – IOS Press and the authors. All rights reserved