title: Developmental regulation of GTP-CH1 in the porcine lung and its relationship to pulmonary vascular relaxation.
abstract: Nitric oxide (NO) plays an important role in lowering pulmonary vascular resistance after birth. However, in persistent pulmonary hypertension of the newborn (PPHN) NO-mediated dilation is dysfunctional. GTP-cyclohydrolase 1 (GTP-CH1) is the rate-limiting enzyme for the biosynthesis of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) an essential cofactor for nitric oxide synthase (NOS) activity. Suboptimal levels of BH4 may result in NOS uncoupling and the subsequent generation of harmful superoxide anions. We therefore investigated the functional effects of supplementing BH4 and/or a superoxide dismutase mimetic (MnTMPyP) in porcine intrapulmonary arteries from normal animals and from a porcine model of PPHN. We investigated whether any functional effects of BH4 could be explained by changes in GTP-CH1 expression. Supplementation of BH4 significantly improved endothelium-dependent relaxations in arteries from 3- and 14-d-old healthy animals, whereas no effect was seen in vessels from younger animals and adults. GTP-CH1 protein expression was lowest at 3 and 14 d, suggesting a rate limitation of BH4 at this time. BH4 supplementation alone did not improve the relaxant response to acetylcholine in arteries obtained in a porcine model of PPHN. Furthermore, GTP-CH1 protein expression was normal for age. However, co-treatment with both BH4 and MnTMPyP restored endothelial function. GTP-CH1 is developmentally regulated in the pulmonary vasculature of neonates and this results in a functionally significant limitation of BH4. Although GTP-CH-1/BH4 levels alone do not explain the profound endothelial dysfunction seen in PPHN, increasing NO bioavailability by supplementing BH4 and quenching superoxide may prove to be therapeutically beneficial.
authors.affiliation: Division of Medicine, British Heart Foundation Labortories, The Rayne Institute, University College London, London, WC1E 6JJ, United Kingdom. m.nandi@ucl.ac.uk
authors.forename: Manasi
authors.initials: M
authors.lastname: Nandi
authors.forename: James
authors.initials: J
authors.lastname: Leiper
authors.forename: Francesca
authors.initials: F
authors.lastname: Arrigoni
authors.forename: Alison
authors.initials: A
authors.lastname: Hislop
authors.forename: Patrick
authors.initials: P
authors.lastname: Vallance
authors.forename: Sheila
authors.initials: S
authors.lastname: Haworth
mesh_terms: D000818:Animals; D006136:GTP Cyclohydrolase / Q000378:metabolism*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008168:Lung / Q000098:blood supply / Q000201:enzymology* / Q000378:metabolism; D011622:Pterins / Q000494:pharmacology; D013552:Swine; D014664:Vasodilation
chemical_list: D011622:Pterins; C016727:sepiapterin; D006136:GTP Cyclohydrolase