on October 18, 2004
Published online before print October 18, 2004, doi: 10.1161/01.CIR.0000145608.80855.BC
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Submitted on March 15, 2004
From the Unit of Pharmacology and Therapeutics (P.B.M., C.D., F.D., M.P., C.B., O.F., J.-L.B.), FATH 5349, Unit of Cardiology (X.H.), Department of Medicine, Unit of Anatomopathology (P.M., Y.G.), Université Catholique de Louvain, Brussels, Belgium, and Division of Cardiology (S.J.), Katholieke Universiteit Leuven, Leuven, Belgium. * To whom correspondence should be addressed. E-mail: balligand{at}mint.ucl.ac.be.
Background--In the heart, nitric oxide synthases (NOS) modulate cardiac contraction in an isoform-specific manner, which is critically dependent on their cellular and subcellular localization. Defective NO production by NOS3 (endothelial NOS [eNOS]) in the failing heart may precipitate cardiac failure, which could be reversed by overexpression of NOS3 in the myocardium. Methods and Results--We studied the influence of NOS3 in relation to its subcellular localization on the function of cardiomyocytes isolated from transgenic mice overexpressing NOS3 under the Conclusions--Moderate overexpression of NOS3, targeted to caveolae in murine cardiomyocytes, potentiates the postsynaptic muscarinic response and attenuates the effect of high concentrations of catecholamines. Cardiomyocyte NOS3 may represent a promising therapeutic target to restore the sympathovagal balance and protect the heart against arrhythmia.
Revised on June 10, 2004
Accepted on June 17, 2004
Cardiomyocyte-Restricted Overexpression of Endothelial Nitric Oxide Synthase (NOS3) Attenuates
Paul B. Massion MD, 
-Adrenergic Stimulation and Reinforces Vagal Inhibition of Cardiac Contraction
-myosin heavy chain promoter (NOS3-TG). Immunoblot analysis demonstrated moderate (5-fold) NOS3 overexpression in cardiomyocytes from NOS3-TG heterozygotes. Caveolar localization of transgenic eNOS was demonstrated by immunofluorescence, coimmunoprecipitation with caveolin-3, sucrose gradient fractionation, and immunogold staining revealed by electron microscopy. Compared with wild-type littermate, contractility of NOS3-TG cardiomyocytes analyzed by videomicroscopy revealed a lower incidence of spontaneous arrhythmic contractions (n=32, P<0.001); an attenuation of the 
-adrenergic positive inotropic response (isoproterenol, 10-7 mol/L: 62.1±7.8% versus 90.8±8.0% of maximum Ca2+ response; n=10 to 17; P<0.05); a potentiation of the muscarinic negative chronotropic response (carbamylcholine, 3.10-8 mol/L: -63.9±14% versus -27.7±5.6% of basal rate; n=8 to 10; P<0.05), confirmed by telemetry in vivo; and an attenuation of the accentuated antagonism of -adrenergically stimulated contraction (-14.6±1.5% versus -3.5±1.5; n=7 to 11; P<0.05). Cardiomyocyte NOS inhibition reversed all 4 effects (P<0.05).
Key words: contractility • nitric oxide synthase • arrhythmia • acetylcholine • catecholamines
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