Document Detail


Myocardial contractile function and heart rate in mice with myocyte-specific overexpression of endothelial nitric oxide synthase.
MedLine Citation:
PMID:  11748107     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: The major source of nitric oxide (NO) in the heart is the constitutive form of NO synthases (eNOS, NOS III) that is expressed in vascular endothelium and cardiac myocytes. NO mediates endothelium-dependent vasodilation and may modulate cardiac function. We examined the role of NO in hearts from transgenic (TG) mice overexpressing eNOS exclusively in cardiac myocytes. METHODS AND RESULTS: Three independent TG lines with varying levels of NOS activity were selected, and the hearts were isolated and retrogradely perfused at constant flow. We found that NO is positively inotropic in spontaneously beating hearts from wild-type (WT) mice, whereas hearts overexpressing eNOS had reduced basal contractility that was partially reversed by NOS blockade. Heart rate was not altered. Acetylcholine (10 to 1000 nmol/L) increased contractility in unstimulated hearts and decreased contractility after beta-adrenergic stimulation with norepinephrine, and these responses were identical in WT and TG hearts. Finally, resting systolic intracellular calcium (Ca(2+)(i)) tended to be lower in TG than in WT hearts, and the beat-to-beat responsiveness to Ca(2+)(i) was reduced in hearts with eNOS overexpression. CONCLUSIONS: High levels of endogenous myocyte-derived NO blunt myofilament Ca(2+) sensitivity. The similar effects of acetylcholine on contractility and heart rate, as well as the identical basal intrinsic heart rate in WT and TG hearts, provide a solid argument against NO as an important modulator of neurohormonal control of myocardial function.
Authors:
F Brunner; P Andrew; G Wölkart; R Zechner; B Mayer
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Circulation     Volume:  104     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2001 Dec 
Date Detail:
Created Date:  2001-12-18     Completed Date:  2002-01-11     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3097-102     Citation Subset:  AIM; IM    
Affiliation:
Institut für Pharmakologie und Toxikologie, the Institut für Molekularbiologie, Biochemie und Mikrobiologie, Karl-Franzens-Universität Graz, Graz, Austria. friedrich.brunner@kfunigraz.ac.at
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MeSH Terms
Descriptor/Qualifier:
Acetylcholine / pharmacology
Animals
Calcium / metabolism,  pharmacology
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology
Female
Gene Expression Regulation, Enzymologic
Genotype
Heart Rate / drug effects,  physiology*
Heart Ventricles / drug effects
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
Mice, Transgenic
Myocardial Contraction / drug effects,  physiology*
Myocardium / enzymology,  metabolism*
NG-Nitroarginine Methyl Ester / pharmacology
Nitric Oxide Synthase / antagonists & inhibitors,  genetics,  metabolism*
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III
Norepinephrine / pharmacology
Vasoconstrictor Agents
Vasodilator Agents / pharmacology
Ventricular Function
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Vasoconstrictor Agents; 0/Vasodilator Agents; 50903-99-6/NG-Nitroarginine Methyl Ester; 51-41-2/Norepinephrine; 51-84-3/Acetylcholine; 7440-70-2/Calcium; EC 1.14.13.39/NOS3 protein, human; EC 1.14.13.39/Nitric Oxide Synthase; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 1.14.13.39/Nos3 protein, mouse
Comments/Corrections
Comment In:
Circulation. 2002 Jul 9;106(2):e5; author reply e5   [PMID:  12105173 ]

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