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Tetrahydrobiopterin analogues with NO-dependent pulmonary vasodilator properties.
MedLine Citation:
PMID:  20950600     Owner:  NLM     Status:  In-Process    
Abstract/OtherAbstract:
Reduced NO levels due to the deficiency of tetrahydrobiopterin (BH(4)) contribute to impaired vasodilation in pulmonary hypertension. Due to the chemically unstable nature of BH(4), it was hypothesised that oxidatively stable analogues of BH(4) would be able to support NO synthesis to improve endothelial dysfunction in pulmonary hypertension. Two analogues of BH(4), namely 6-hydroxymethyl pterin (HMP) and 6-acetyl-7,7-dimethyl-7,8-dihydropterin (ADDP), were evaluated for vasodilator activity on precontracted rat pulmonary artery rings. ADDP was administered to pulmonary hypertensive rats, followed by measurement of pulmonary vascular resistance in perfused lungs and eNOS expression by immunohistochemistry. ADDP and HMP caused significant relaxation in vitro in rat pulmonary arteries depleted of BH(4) with a maximum relaxation at 0.3μM (both P<0.05). Vasodilator activity of ADDP and HMP was completely abolished following preincubation with the NO synthase inhibitor, L-NAME. ADDP and HMP did not alter relaxation induced by carbachol or spermine NONOate. BH(4) itself did not produce relaxation. In rats receiving ADDP 14.1mg/kg/day, pulmonary vasodilation induced by calcium ionophore A23187 was augmented and eNOS immunoreactivity was increased. In conclusion, ADDP and HMP are two analogues of BH(4), which can act as oxidatively stable alternatives to BH(4) in causing NO-mediated vasorelaxation. Chronic treatment with ADDP resulted in improvement of NO-mediated pulmonary artery dilation and enhanced expression of eNOS in the pulmonary vascular endothelium. Chemically stable analogues of BH(4) may be able to limit endothelial dysfunction in the pulmonary vasculature.
Authors:
Suma P Kunuthur; Philip H Milliken; Colin L Gibson; Colin J Suckling; Roger M Wadsworth
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-10-13
Journal Detail:
Title:  European journal of pharmacology     Volume:  650     ISSN:  1879-0712     ISO Abbreviation:  Eur. J. Pharmacol.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2010-12-06     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  1254354     Medline TA:  Eur J Pharmacol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  371-7     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier B.V. All rights reserved.
Affiliation:
Strathclyde Institute of Pharmacy and Biomedical Sciences, UK.
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MeSH Terms
Descriptor/Qualifier:
Grant Support
ID/Acronym/Agency:
FS2001056//British Heart Foundation

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