title: Tetrahydrobiopterin improves endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women.
abstract: The mechanisms mediating arterial stiffening with aging and menopause are not completely understood. We determined whether administration of tetrahydrobiopterin (BH(4)), a critical cofactor for endothelial nitric oxide synthase to produce nitric oxide, would increase vascular endothelial-dependent vasodilatory tone and decrease arterial stiffness in estrogen-deficient postmenopausal women. Additionally, we examined whether the beneficial effects of estrogen on vascular function were possibly related to BH(4). Arterial stiffness (carotid artery compliance) and endothelial-dependent vasodilation [brachial artery flow-mediated dilation (FMD)] were measured in postmenopausal (n = 24; 57 ± 1 yr, mean ± SE) and eumenorrheic premenopausal (n = 9; 33 ± 2 yr) women before and 3 h after the oral administration of BH(4). Subsequently, in postmenopausal women, vascular testing (before and after BH(4)) was repeated following randomization to either 2 days of transdermal estradiol or placebo. Baseline carotid artery compliance and brachial artery FMD were lower in postmenopausal than in premenopausal women (P < 0.0001). BH(4) administration increased carotid artery compliance (0.61 ± 0.05 to 0.73 ± 0.04 mm(2)·mmHg(-1)·10(-1) vs. baseline, P < 0.0001) and brachial artery FMD (P < 0.001) in postmenopausal women but had no effect in premenopausal women (P = 0.62). Carotid artery compliance (0.59 ± 0.05 to 0.78 ± 0.06 mm(2)·mmHg(-1)·10(-1), P < 0.001) and FMD increased in postmenopausal women in response to estradiol (P = 0.02) but were not further improved with the coadministration of BH(4), possibly because estrogen increased BH(4) bioavailability. Carotid artery compliance and FMD increased with BH(4) in the placebo group (P = 0.02). Although speculative, these results suggest that reduced vascular BH(4) may be an important contributor to arterial stiffening in estrogen-deficient postmenopausal women, related in part to reduced endothelial-dependent vasodilatory tone.
authors.affiliation: Divisions of Geriatric Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Kerrie.Moreau@UCDenver.edu
authors.forename: Kerrie L
authors.initials: KL
authors.lastname: Moreau
authors.forename: Amie
authors.initials: A
authors.lastname: Meditz
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Deane
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Kohrt
mesh_terms: D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives*; D001916:Brachial Artery / Q000187:drug effects / Q000502:physiology; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D006801:Humans; D008875:Middle Aged; D017698:Postmenopause / Q000187:drug effects* / Q000502:physiology; D059289:Vascular Stiffness / Q000187:drug effects* / Q000502:physiology; D014664:Vasodilation; D014665:Vasodilator Agents / Q000008:administration & dosage*
chemical_list: D004967:Estrogens; D014665:Vasodilator Agents; D001708:Biopterins; D004958:Estradiol; C003402:sapropterin