No effect of acute tetrahydrobiopterin (BH4) supplementation on vascular dysfunction in the old

Abstract

As a deficiency in tetrahydrobiopterin (BH₄), a cofactor for endothelial nitric oxide synthase, has been implicated in the age-related decline in vascular function, this study aimed to determine the impact of acute BH₄ supplementation on flow-mediated vasodilation (FMD) in old adults. Two approaches were used: 1) A multiday, double-blind, placebo-controlled, crossover design measuring, FMD [ΔFMD (mm), %FMD (%)] and shear rate area under the curve (SR AUC) in nine old subjects (73 ± 8 yr) with either placebo (placebo) or BH₄ (≈10 mg/kg, post), and 2) a single experimental day measuring FMD in an additional 13 old subjects (74 ± 7 yr) prior to (pre) and 4.5 h after ingesting BH₄ (≈10 mg/kg). With the first experimental approach, acute BH₄ intake did not significantly alter FMD (ΔFMD: 0.17 ± 0.03 vs. 0.13 ± 0.02 mm; %FMD: 3.3 ± 0.61 vs. 2.9 ± 0.4%) or SR AUC (30,280 ± 4,428 vs. 37,877 ± 9,241 s^-1) compared with placebo. Similarly, with the second approach, BH₄ did not significantly alter FMD (ΔFMD: 0.09 ± 0.02 vs. 0.12 ± 0.03 mm; %FMD: 2.2 ± 0.6 vs. 2.9 ± 0.6%) or SR AUC (37,588 ± 6,753 vs. 28,996 ± 3,735 s^-1) compared with pre. Moreover, when the two data sets were combined, resulting in a greater sample size, there was still no evidence of an effect of BH₄ on vascular function in these old subjects. Importantly, both plasma BH₄ and 7,8-dihydrobiopterin (BH2), the oxidized form of BH₄, increased significantly with acute BH₄ supplementation. Consequently, the ratio of BH₄/BH₂, recognized to impact vascular function, was unchanged. Thus, acute BH₄ supplementation does not correct vascular dysfunction in the old.NEW & NOTEWORTHY Despite two different experimental approaches, acute BH₄ supplementation did not affect vascular function in older adults, as measured by flow-mediated vasodilation. Plasma levels of both BH₄ and BH₂, the BH₄ oxidized form, significantly increased after acute BH₄ supplementation, resulting in an unchanged ratio of BH₄/BH₂, a key determining factor for endothelial nitric oxide synthase coupling. Therefore, likely due to the elevated oxidative stress with advancing age, acute BH₄ supplementation does not correct vascular dysfunction in the old.

Keywords: BH2; FMD; aging; shear rate; vascular function.