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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
8
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pubmed:dateCreated |
2001-1-26
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pubmed:abstractText |
The 4-amino analogue of tetrahydrobiopterin (4-ABH(4)) is a potent pterin-site inhibitor of nitric oxide synthases (NOS). Although 4-ABH(4) does not exhibit selectivity between purified NOS isoforms, a pronounced selectivity of the drug towards inducible NOS (iNOS) is apparent in intact cells. This work was carried out to investigate the potential iNOS selectivity of 4-ABH(4) in isolated pig pulmonary and coronary arteries. Endothelium-dependent relaxations of pig pulmonary and coronary artery strips to bradykinin or calcium ionophore A23187 were inhibited by 4-ABH(4) in a concentration-dependent manner. Half-maximal inhibition was observed at 60 - 65 microM (pulmonary artery) and 200 - 250 microM 4-ABH(4) (coronary artery). Pig coronary artery strips precontracted with 0.1 microM 9, 11-dideoxy-9, 11-methanoepoxy-prosta-glandin F(2alpha) (U46619) showed a time-dependent relaxation (monitored for up to 18 h) upon incubation with 1 microg ml(-1) lipopolysaccharide (LPS). Addition of 10 microM 4-ABH(4) 1 h after LPS led to a pronounced inhibition of the LPS-triggered relaxation, whereas the pterin antagonist had no effect when given> or =4 h after LPS. Incubation of pulmonary and coronary artery strips with 1 microg ml(-1) LPS attenuated contractile responses to norepinephrine (1 microM) and U46619 (0.1 microM). This hyporeactivity of the blood vessels to vasoconstrictor agents was inhibited by 4-ABH(4) in a concentration-dependent manner [IC(50)=17.5+/-5.9 microM (pulmonary artery) and 20.7+/-3 microM (coronary artery)]. The effect of 0.1 mM 4-ABH(4) was antagonized by coincubation with 0.1 mM sepiapterin, which is known to supply intracellular BH(4) via a salvage pathway. These results demonstrate that 4-ABH(4) is a fairly selective inhibitor of iNOS in an in vitro model of endotoxaemia, suggesting that this drug and/or related pterin-site NOS inhibitors may be useful to increase blood pressure in severe infections associated with a loss of vascular responsiveness to constrictor agents caused by endotoxin-triggered iNOS induction in the vasculature.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/11139456-10362413,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11139456-10443572,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11139456-10514281,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11139456-10519554,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11139456-10608822,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/11139456-1852778,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11139456-2124251,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11139456-2162040,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/11139456-9927704
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/1,1-diethyl-2-hydroxy-2-nitrosohydra...,
http://linkedlifedata.com/resource/pubmed/chemical/15-Hydroxy-11 alpha,9...,
http://linkedlifedata.com/resource/pubmed/chemical/4-amino-tetrahydrobiopterin,
http://linkedlifedata.com/resource/pubmed/chemical/5,6,7,8-tetrahydrobiopterin,
http://linkedlifedata.com/resource/pubmed/chemical/Biopterin,
http://linkedlifedata.com/resource/pubmed/chemical/Bradykinin,
http://linkedlifedata.com/resource/pubmed/chemical/Calcimycin,
http://linkedlifedata.com/resource/pubmed/chemical/Endotoxins,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Hydrazines,
http://linkedlifedata.com/resource/pubmed/chemical/Lipopolysaccharides,
http://linkedlifedata.com/resource/pubmed/chemical/Nitric Oxide Donors,
http://linkedlifedata.com/resource/pubmed/chemical/Nitric Oxide Synthase,
http://linkedlifedata.com/resource/pubmed/chemical/Nitric Oxide Synthase Type II,
http://linkedlifedata.com/resource/pubmed/chemical/Nitroarginine,
http://linkedlifedata.com/resource/pubmed/chemical/Nitrogen Oxides,
http://linkedlifedata.com/resource/pubmed/chemical/Norepinephrine,
http://linkedlifedata.com/resource/pubmed/chemical/Pteridines,
http://linkedlifedata.com/resource/pubmed/chemical/Pterins,
http://linkedlifedata.com/resource/pubmed/chemical/Vasoconstrictor Agents,
http://linkedlifedata.com/resource/pubmed/chemical/sepiapterin
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
0007-1188
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
131
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1757-65
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
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