Administration of tetrahydrobiopterin improves the microcirculation and outcome in an ovine model of septic shock*

Abstract

In this clinically relevant model of sepsis, tetrahydrobiopterin supplementation attenuated the impairment in sublingual microvascular perfusion and permeability, which was accompanied by better preserved gas exchange, renal flow and urine output, and prolonged survival.

Tetrahydrobiopterin in Cardiovascular Health and Disease

“…BH4 treatment, in addition to attenuating the decreases in cardiac index and blood pressure, maintained small vessel perfusion and microvascular flow index. Increased survival in the BH4-treated animals was accompanied by preserved gas exchange and kidney function (101).…”

“…To address whether BH4 has any potential to cause a positive modification of sepsis through effects on the microcirculation, tetrahydrobiopterin supplementation in an ovine model of peritoneal sepsis has been evaluated. Sheep received two bolus treatments with BH4 during the induction of sepsis through an injection of fecal material into the peritoneum (101). BH4 treatment, in addition to attenuating the decreases in cardiac index and blood pressure, maintained small vessel perfusion and microvascular flow index.…”

The Microcirculation of the Septic Kidney

“…Moreover, during sepsis, there is a depletion of tetrahydrobiopterin, a substrate needed for eNOS. 33 Ischemicinduced activation of inducible NO synthase (iNOS) in leukocytes, vascular smooth muscle cells, and epithelial tubular cells also participates in vascular dysfunction. 34 The two main pathways of iNOSderived NO generation are thought to be the inhibition of eNOS-derived NO generation and the formation of reactive oxygen species (ROS), such as peroxynitrite.…”

The Effects of Fenoldopam on Renal Function and Metabolism in an Ovine Model of Septic Shock

“…1). Sepsis was then induced by injection of 1.5 g/kg autologous feces into the abdominal cavity (T0, baseline) (16,17). After 2 h, the animals were randomly allocated by the envelope method to receive either fenoldopam at a dose of 1.0 mg/kg/min (low-dose; n ¼ 5) or placebo (NaCl 0.9%, control; n ¼ 5) at an equal infusionrate of 7 to 10 mL/h.…”