The effect of tetrahydrobiopterin on microvascular function with advancing age assessed by passive leg movement

Abstract

Tetrahydrobiopterin (BH4) is a cofactor which recouples eNOS, potentially increasing nitric oxide (NO)‐bioavailability. Previously, BH4 has been documented to restore conduit artery vascular dysfunction, assessed by flow mediated vasodilation (FMD) in sedentary old subjects. This study aimed to determine if BH4 can restore microvascular function in the old, assessed by the, highly NO‐dependent, passive leg movement (PLM) test. Two approaches were employed, with the first recapitulating the experimental design of the prior FMD study: 1) Using a double‐blind, placebo controlled, crossover design, eight old subjects (74±8 yrs) ingested BH4 (100mg/kg) or placebo on two different days at least one week apart, with PLM assessed (blood flow ΔPeak and AUC) after both conditions. 2) On a single experimental day, PLM was assessed in an additional thirteen old subjects (74±8 yrs) prior to and ~ 4.5 hours after ingesting BH4 (100 mg/kg). With the first experimental approach, BH4 increased PLM ΔPeak and AUC by ≈20% (271±94 vs 326±158) and ≈29% (60±40 vs 77±51), respectively, compared to placebo, but did not achieve statistical significance. With the second approach, BH4 increased PLM ΔPeak and AUC ≈30% (323±182 vs 421±192; p=0.01) and ≈38% (64±62 vs 89±56; p=0.06), respectively. When the two data sets were combined, BH4 significantly increased both PLM ΔPeak ≈28%(305±156 vs 388±183; p=0.01) and AUC ≈43%(63±54 vs 85±53; p=0.02). Thus, improving eNOS‐recoupling with acute BH4 supplementation can improve microvascular function with advancing age and this is likely a result of increased NO‐bioavailability.