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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
9
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pubmed:dateCreated |
2003-10-31
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pubmed:abstractText |
Nitrate tolerance (NT) in hypertension is attributed to reduced activity of soluble guanylyl cyclase (sGC). We examined NT in basilar artery vascular smooth muscle cells (VSMCs) from control rats, rats infused with angiotensin II (Ang; 240 microg/kg per hour for 4 days), which were normotensive, and Ang-hypertensive rats (AHR; 240 microg/kg per hour for 28 days). Ca2+-activated K+ (Maxi-K) channels in VSMCs from AHR showed reduced activation by NO donor, consistent with NT. The concentration-response relationship for 8-Br-cGMP was shifted 2.5-fold to the right, indicating that abnormal sGC alone could not account for NT. Inside-out patches from AHR showed normal activation with exogenous cGMP-dependent protein kinase I (cGKI), suggesting no abnormality downstream of cGKI. We hypothesized that the reduction in apparent affinity of 8-Br-cGMP for cGKI in AHR might be due to a change in relative amounts of cGKIalpha versus cGKIbeta, since cGKIbeta is less sensitive to cGMP activators than cGKIalpha. This was substantiated by showing the following in AHR: (1) reduced effect of the cGKIalpha-selective activator 8-APT-cGMP; (2) reduced total cGKI protein (both isoforms), but an increase in cGKIbeta protein in quantitative immunofluorescence and Western blots; (3) similar changes in cGKI isoforms immunoisolated with Maxi-K channels; and (4) a large increase in cGKIbeta mRNA and a decrease in cGKIalpha mRNA in real-time PCR and Northern blots. Upregulation of cytosolic cGKIbeta was evident 4 days after Ang infusion, before development of hypertension. Our data identify a functional role for cGKIbeta in VSMCs previously ascribed exclusively to cGKIalpha. Ang-induced alternative splicing of cGKI represents a novel mechanism for reducing sensitivity to NO/cGMP.
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pubmed:grant |
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pubmed:commentsCorrections |
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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/8-bromocyclic GMP,
http://linkedlifedata.com/resource/pubmed/chemical/Angiotensins,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclic GMP,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclic GMP-Dependent Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Guanylate Cyclase,
http://linkedlifedata.com/resource/pubmed/chemical/Isoenzymes,
http://linkedlifedata.com/resource/pubmed/chemical/Large-Conductance...,
http://linkedlifedata.com/resource/pubmed/chemical/Nitrates,
http://linkedlifedata.com/resource/pubmed/chemical/Nitric Oxide,
http://linkedlifedata.com/resource/pubmed/chemical/Nitric Oxide Donors,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphoric Diester Hydrolases,
http://linkedlifedata.com/resource/pubmed/chemical/Potassium Channels...,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase C,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Cytoplasmic and Nuclear,
http://linkedlifedata.com/resource/pubmed/chemical/cGMP-dependent protein kinase Ialpha,
http://linkedlifedata.com/resource/pubmed/chemical/soluble guanylyl cyclase
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
1524-4571
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
31
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pubmed:volume |
93
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
805-12
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:14512447-Alternative Splicing,
pubmed-meshheading:14512447-Angiotensins,
pubmed-meshheading:14512447-Animals,
pubmed-meshheading:14512447-Blood Pressure,
pubmed-meshheading:14512447-Cell Separation,
pubmed-meshheading:14512447-Cyclic GMP,
pubmed-meshheading:14512447-Cyclic GMP-Dependent Protein Kinases,
pubmed-meshheading:14512447-Disease Models, Animal,
pubmed-meshheading:14512447-Disease Progression,
pubmed-meshheading:14512447-Dose-Response Relationship, Drug,
pubmed-meshheading:14512447-Drug Tolerance,
pubmed-meshheading:14512447-Female,
pubmed-meshheading:14512447-Guanylate Cyclase,
pubmed-meshheading:14512447-Hypertension,
pubmed-meshheading:14512447-Isoenzymes,
pubmed-meshheading:14512447-Large-Conductance Calcium-Activated Potassium Channels,
pubmed-meshheading:14512447-Muscle, Smooth, Vascular,
pubmed-meshheading:14512447-Nitrates,
pubmed-meshheading:14512447-Nitric Oxide,
pubmed-meshheading:14512447-Nitric Oxide Donors,
pubmed-meshheading:14512447-Patch-Clamp Techniques,
pubmed-meshheading:14512447-Phosphoric Diester Hydrolases,
pubmed-meshheading:14512447-Potassium Channels, Calcium-Activated,
pubmed-meshheading:14512447-Protein Kinase C,
pubmed-meshheading:14512447-RNA, Messenger,
pubmed-meshheading:14512447-Rats,
pubmed-meshheading:14512447-Rats, Inbred WKY,
pubmed-meshheading:14512447-Receptors, Cytoplasmic and Nuclear
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pubmed:year |
2003
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pubmed:articleTitle |
Alternative splicing of cGMP-dependent protein kinase I in angiotensin-hypertension: novel mechanism for nitrate tolerance in vascular smooth muscle.
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pubmed:affiliation |
Department of Neurosurgery, University of Maryland at Baltimore, Baltimore, Md, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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