The Unknown Mechanism of Exogenous Tetrahydrobiopterin in the Renal Protection of Sheep Ischemia and Reperfusion

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Rahmania et al1 demonstrated a potentially beneficial effect of tetrahydrobiopterin (BH4) administration in the sheep model of renal ischemia/reperfusion.1 BH4 is one of the critical cofactors activating nitric oxide synthase,2 and therefore they conceived the idea that the exogenously applied BH4 might enhance the pathway resulting in protection of organs from ischemia/reperfusion. Indeed, BH4 treatment reduced renal microvascular injury and improved renal metabolism and function, but they did not evaluate in renal tissue the levels of BH4, as well as dihydrobiopterin (BH2), which is an oxidized form of BH4.
The effects of BH4 appear unrelated to augmentation of nitric oxide synthase activity for the following reasons. Exogenous application of BH4 to cells is susceptible to auto-oxidation resulting in the production of superoxide, which actively converts nitric oxide to peroxynitrite. BH4 requires oxidation to BH2 to diffuse into cells.2,3 For these reasons, the measurements of BH4 levels, as well as BH2 within cells or organs, are critical to judging the intracellular effect of BH4.2 Indeed, a previous clinical study demonstrated that oral BH4 treatment augments total biopterin levels in patients with coronary artery disease, whereas it has no beneficial effect on endothelial function due to systemic oxidation of BH4.4 Therefore, we have to await additional data to verify the mechanism of BH4’s impact in the study by Rahmania et al.
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