Effects of supplementation of BH₄ after prolonged ischemia in skeletal muscle

Abstract

Supplementation of BH(4) during reperfusion provided a significant protection against I/R injury in rat skeletal muscle.

Reperfusion injury and reactive oxygen species: The evolution of a concept

“…Similarly, substrates for BH 4 synthesis (sepiaterin and folate) have been shown to protect against I/R-induced myocardial inflammation and contractile dysfunction [428] , [429] . Similar observations have been noted in I/R models in the kidney [430] , liver [431] , and skeletal muscle [432] . Finally, if BH 4 levels are reduced and eNOS is uncoupled prior to I/R, the resultant injury responses in both liver and heart are exacerbated [433] .…”

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

“…This improvement in tissue oxygen availability was also reflected by the blunted decrease in venous blood oxygen saturation, the blunted increase in oxygen extraction index, and the delayed increase in blood lactate levels. These results in this large animal model of sepsis are in line with findings that BH4 can improve the microcirculation in endotoxic rodents (20,24) and in ischemia-reperfusion injury (20,24), and with the observations that BH4 administration restored forearm blood flow reactivity in healthy volunteers challenged by small doses of endotoxin or oral glucose (22,33). In addition to microcirculatory changes, the improved tissue oxygen availability may also be related to effects of BH4 on other factors, including mitochondrial function, which should be evaluated in further studies.…”

“…Exogenous BH4 may exert beneficial effects by restoring coupling of eNOS and attenuating oxidative stress. In experimental models of ischemia/ reperfusion injury, BH4 administration improved microvascular perfusion (19,20). In patients with coronary artery disease, intracoronary infusion of BH4 improved acetylcholine-induced microvascular flow response (21).…”

Transgenic overexpression of GTP cyclohydrolase 1 in cardiomyocytes ameliorates post-infarction cardiac remodeling

“…In rats or pigs, the administration of either BH 4 before ischemia or the combination of BH 4 and L-arginine prior to post-ischemic reperfusion significantly reduced myocardial infarct size 64, 65 . In addition to the heart, the administration of either BH 4 or sepiapterin, the precursor of BH 4 , prior to ischemia protects the liver, kidneys, and skeletal muscle against I/R injury 66–70 . In humans, the co-administration of BH 4 and L-arginine attenuates endothelial dysfunction induced by forearm ischemia and reperfusion in patients with coronary artery disease and type 2 diabetes mellitus 71 .…”