Tetrahydrobiopterin Administration Augments Exercise-Induced Hyperemia and Endothelial Function in Patients With...

Systemic sclerosis (SSc) is a rare, auto-immune disease with variably progressive fibrosis of the skin and internal organs, as well as vascular dysfunction. Recently, we demonstrated a decrement in exercising skeletal muscle blood flow and endothelium-dependent vasodilation in SSc, but the mechanisms responsible for these impairments have not been investigated. Thus, we sought to determine if acute administration of tetrahydrobiopterin (BH₄), an essential cofactor for endothelial nitric oxide synthase (eNOS), would improve hyperemia and brachial artery vasodilation during progressive handgrip exercise in SSc. Thirteen patients with SSc (63 ± 11 years) participated in this placebo-controlled, randomized, double-blind, crossover study. Tetrahydrobiopterin (10 mg/kg) administration resulted in a ~4-fold increase in circulating BH₄ concentrations (P < 0.05). Cardiovascular variables at rest were unaffected by BH₄ (P > 0.05). During handgrip exercise, BH₄ administration increased brachial artery blood flow (placebo: 200 ± 87; BH₄: 261 ± 115 ml/min; P < 0.05) and vascular conductance (placebo: 2.0 ± 0.8; BH₄: 2.5 ± 1.0 ml/min/mmHg; P < 0.05), indicating augmented resistance artery vasodilation. Tetrahydrobiopterin administration also increased brachial artery vasodilation in response to exercise (placebo: 12 ± 6; BH₄: 17 ± 7%; P < 0.05), resulting in a significant upward shift in the slope relationship between Δ brachial artery vasodilation and Δ shear rate (placebo: 0.030 ± 0.007; BH₄: 0.047 ± 0.007; P < 0.05) that indicates augmented sensitivity of the brachial artery to vasodilate to the sustained elevations in shear rate during handgrip exercise. These results demonstrate the efficacy of acute BH₄ administration to improve both resistance and conduit vessel endothelial function in SSc, suggesting that eNOS recoupling may be an effective strategy for improving vasodilatory capacity in this patient group.