Abstract:
:Nitric oxide (NO) functions principally as a diffusible paracrine effector. The exception is in cardiomyocytes where both NO synthases (NOS) and target proteins coexist, allowing NO to work in an autocrine/intracrine fashion. However, the most abundant myocyte isoform (NOS3) is far more expressed in vascular endothelium; thus, the in vivo contribution of myocyte-NOS3 remains less clear. The present study tested this role by transfecting whole hearts of NOS3-null (NOS3(-/-)) mice with adenovirus-expressing NOS3 coupled to a alpha-MHC promoter (AdV(NOS3)), comparing results to hearts transfected with marker-gene beta-galactosidase (AdVbeta(gal)). Total myocardial NOS3 protein and activity were restored to near wild-type (WT) levels in NOS3(-/-)+AdV(NOS3) hearts, and NOS3 relocalized normally with caveolin-3. Ejection function by pressure-volume analysis was enhanced in NOS3(-/-)+AdVbeta(gal) over WT or NOS3(-/-)+AdV(NOS3). More prominently, isoproterenol (ISO)-stimulated systolic and diastolic function in WT was amplified in NOS3(-/-)+AdVbeta(gal), whereas NOS3(-/-)+AdV(NOS3) returned the response to control. ISO-activated systolic function was inhibited 85% by concomitant muscarinic stimulation (carbachol) in NOS3(-/-)+AdV(NOS3) but not NOS3(-/-)+AdVbeta(gal) hearts. Lastly, NOS3(-/-)+AdVbeta(gal) mice displayed enhanced inotropy and lusitropy over WT at slower heart rates but a blunted rate augmentation versus controls. A more positive rate response was restored in NOS3(-/-)+AdV(NOS3) (P<0.001). Thus, myocyte autocrine/intracrine NOS3 regulation in vivo can underlie key roles in beta-adrenergic, muscarinic, and frequency-dependent cardiac regulation.
journal_name
Circ Resjournal_title
Circulation researchauthors
Champion HC,Georgakopoulos D,Takimoto E,Isoda T,Wang Y,Kass DAdoi
10.1161/01.RES.0000119323.79644.20subject
Has Abstractpub_date
2004-03-19 00:00:00pages
657-63issue
5eissn
0009-7330issn
1524-4571pii
01.RES.0000119323.79644.20journal_volume
94pub_type
杂志文章abstract:RATIONALE:In ventricular myocytes of large mammals with low T-tubule density, a significant number of ryanodine receptors (RyRs) are not coupled to the sarcolemma; cardiac remodeling increases noncoupled RyRs. OBJECTIVE:Our aim was to test the hypothesis that coupled and noncoupled RyRs have distinct microdomain-depen...
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更新日期:1997-03-01 00:00:00
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pub_type: 杂志文章,评审
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更新日期:2008-11-21 00:00:00
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pub_type: 杂志文章
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更新日期:1995-10-01 00:00:00
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更新日期:1985-02-01 00:00:00
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pub_type: 杂志文章
doi:10.1161/01.res.52.5.580
更新日期:1983-05-01 00:00:00
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pub_type: 杂志文章
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更新日期:1979-11-01 00:00:00
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pub_type: 杂志文章,评审
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更新日期:2012-01-06 00:00:00
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doi:10.1161/CIRCRESAHA.118.314438
更新日期:2019-04-12 00:00:00
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更新日期:2010-11-12 00:00:00
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更新日期:1999-10-29 00:00:00
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pub_type: 杂志文章
doi:10.1161/01.res.73.5.792
更新日期:1993-11-01 00:00:00
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更新日期:2021-01-22 00:00:00
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更新日期:2019-09-13 00:00:00
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更新日期:2001-06-08 00:00:00
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