Source:http://linkedlifedata.com/resource/pubmed/id/18952768
Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
1
|
| pubmed:dateCreated |
2008-12-22
|
| pubmed:abstractText |
The pathophysiological relevance of endothelial nitric-oxide synthase (eNOS)-induced superoxide production in cardiomyocyte injury after prolonged phenylephrine (PE) exposure remains unclear. The aims of this study were to define the mechanism of O2(*) production by uncoupled eNOS and evaluate the therapeutic potential of a novel calmodulin antagonist 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxyindazole (DY-9836) to rescue hypertrophied cardiomyocytes from PE-induced injury. In cultured rat cardiomyocytes, prolonged exposure for 96 h to PE led to translocation from membrane to cytosol of eNOS and breakdown of caveolin-3 and dystrophin. When NO and O2(*) production were monitored in PE-treated cells by 4-amino-5-methylamino-2',7'-difluorofluorescein and dihydroethidium, respectively, Ca(2+)-induced NO production elevated by 5.7-fold (p < 0.01) after 48-h PE treatment, and the basal NO concentration markedly elevated (16-fold; p < 0.01) after 96-h PE treatment. On the other hand, the O2(*) generation at 96 h was closely associated with an increased uncoupled eNOS level. Coincubation with DY-9836 (3 microM) during the last 48 h inhibited the aberrant O2(*) generation nearly completely and NO production by 72% (p < 0.01) after 96 h of PE treatment and inhibited the breakdown of caveolin-3/dystrophin in cardiomyocytes. PE-induced apoptosis assessed by TdT-mediated dUTP nick-end labeling staining was also attenuated by DY-9836 treatment. These results suggest that O2(*) generation by uncoupled eNOS probably triggers PE-induced cardiomyocyte injury. Inhibition of abnormal O2(*) and NO generation by DY-9836 treatment represents an attractive therapeutic strategy for PE/hypertrophy-induced cardiomyocyte injury.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Calmodulin,
http://linkedlifedata.com/resource/pubmed/chemical/Cardiotonic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Caveolin 3,
http://linkedlifedata.com/resource/pubmed/chemical/Dystrophin,
http://linkedlifedata.com/resource/pubmed/chemical/Fluorescent Dyes,
http://linkedlifedata.com/resource/pubmed/chemical/Indazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Nitric Oxide,
http://linkedlifedata.com/resource/pubmed/chemical/Nitric Oxide Synthase Type III,
http://linkedlifedata.com/resource/pubmed/chemical/Phalloidine,
http://linkedlifedata.com/resource/pubmed/chemical/Phenylephrine,
http://linkedlifedata.com/resource/pubmed/chemical/Piperazines,
http://linkedlifedata.com/resource/pubmed/chemical/Rhodamines,
http://linkedlifedata.com/resource/pubmed/chemical/Superoxides
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Jan
|
| pubmed:issn |
1521-0111
|
| pubmed:author | |
| pubmed:issnType |
Electronic
|
| pubmed:volume |
75
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
101-12
|
| pubmed:meshHeading |
pubmed-meshheading:18952768-Animals,
pubmed-meshheading:18952768-Animals, Newborn,
pubmed-meshheading:18952768-Calmodulin,
pubmed-meshheading:18952768-Cardiotonic Agents,
pubmed-meshheading:18952768-Caveolin 3,
pubmed-meshheading:18952768-Cells, Cultured,
pubmed-meshheading:18952768-Dystrophin,
pubmed-meshheading:18952768-Fluorescent Antibody Technique, Indirect,
pubmed-meshheading:18952768-Fluorescent Dyes,
pubmed-meshheading:18952768-Heart Ventricles,
pubmed-meshheading:18952768-Immunohistochemistry,
pubmed-meshheading:18952768-Indazoles,
pubmed-meshheading:18952768-Myocytes, Cardiac,
pubmed-meshheading:18952768-Nitric Oxide,
pubmed-meshheading:18952768-Nitric Oxide Synthase Type III,
pubmed-meshheading:18952768-Phalloidine,
pubmed-meshheading:18952768-Phenylephrine,
pubmed-meshheading:18952768-Piperazines,
pubmed-meshheading:18952768-Rats,
pubmed-meshheading:18952768-Rats, Wistar,
pubmed-meshheading:18952768-Rhodamines,
pubmed-meshheading:18952768-Superoxides,
pubmed-meshheading:18952768-Time Factors
|
| pubmed:year |
2009
|
| pubmed:articleTitle |
Phenylephrine-induced cardiomyocyte injury is triggered by superoxide generation through uncoupled endothelial nitric-oxide synthase and ameliorated by 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxyindazole (DY-9836), a novel calmodulin antagonist.
|
| pubmed:affiliation |
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
|
| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|