Published online before print January 29, 2004, doi: 10.1161/01.RES.0000119323.79644.20
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Submitted on August 21, 2003
Revised on January 14, 2004
Accepted on January 16, 2004
Modulation of In Vivo Cardiac Function by Myocyte-Specific Nitric Oxide Synthase-3
Hunter C. Champion ;
From the Division of Cardiology (H.C.C., D.A.K.), Department of Medicine (D.G., E.T., T.I.), Johns Hopkins Hospital, Baltimore, Md; and the University of Maryland School of Medicine (Y.W.), Baltimore, Md.
* To whom correspondence should be addressed. E-mail: dkass{at}jhmi.edu.
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 
-MHC promoter (AdVNOS3), comparing results to hearts transfected with marker-gene 
-galactosidase (AdVgal). Total myocardial NOS3 protein and activity were restored to near wild-type (WT) levels in NOS3-/-+AdVNOS3 hearts, and NOS3 relocalized normally with caveolin-3. Ejection function by pressure-volume analysis was enhanced in NOS3-/-+AdVgal over WT or NOS3-/-+AdVNOS3. More prominently, isoproterenol (ISO)-stimulated systolic and diastolic function in WT was amplified in NOS3-/-+AdVgal, whereas NOS3-/-+AdVNOS3 returned the response to control. ISO-activated systolic function was inhibited 85% by concomitant muscarinic stimulation (carbachol) in NOS3-/-+AdVNOS3 but not NOS3-/-+AdVgal hearts. Lastly, NOS3-/-+AdVgal 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-/-+AdVNOS3 (P<0.001). Thus, myocyte autocrine/intracrine NOS3 regulation in vivo can underlie key roles in -adrenergic, muscarinic, and frequency-dependent cardiac regulation.
Key words: nitric oxide synthase • myocyte • adenovirus •
-adrenergic •
hemodynamics
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