Circulation Research. 2002;90:93-99
Published online before print November 26, 2001, doi: 10.1161/hh0102.102757
Published online before print November 26, 2001, doi: 10.1161/hh0102.102757
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© 2002 American Heart Association, Inc.
Integrative Physiology |
Cardiac-Specific Overexpression of Inducible Nitric Oxide Synthase Does Not Result in Severe Cardiac Dysfunction
From the Institut für Herz- und Kreislaufphysiologie (J.H., A.G., U.F., M.W.M., A.M., J.S.), Heinrich-Heine Universität Düsseldorf; Deutsches Diabetes-Forschungsinstitut (W.N.K.-V.), Abteilung für Klinische Biochemie, Düsseldorf, Germany.
Correspondence to Jürgen Schrader, MD, Professor and Chairman, Department of Cardiovascular Physiology, University of Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany. E-mail schrader{at}uni-duesseldorf.de
Nitric oxide (NO), a potent regulator of myocardial contractility, has been implicated in the development of heart failure; however, no study exists describing the relation between expression of inducible nitric oxide synthase (iNOS), formation of NO in vivo, and cardiac contractility. We have therefore generated transgenic (TG) mice overexpressing iNOS under the cardiospecific 
-myosin heavy chain (-MHC) promoter. In vitro, iNOS activity in hearts of two transgenic lines was 260- to 400-fold above controls (wild type [WT]), but TG mice were viable and appeared normal. Ventricular mass/body weight ratio did not differ; heart rate and cardiac output as well as mean arterial blood pressure were decreased by 10%. NOx levels of hearts and blood of TG mice were 2.5- and 2-fold above WT controls, respectively. In the isolated heart, release of the NO oxidation products nitrate and nitrite, an index of in vivo NOS activity, was 40-fold over WT. However, cardiac hemodynamics and levels of ATP and phosphocreatine were unaltered. The high iNOS activity was associated with reduced cardiac L-arginine in TG hearts to only 15% of the WT, indicating limited substrate availability, whereas L-citrulline was 20-fold elevated. Our findings demonstrate that the heart can tolerate high levels of iNOS activity without detrimental functional consequences. The concept that iNOS-derived NO is the triggering factor in the pathomechanism leading to heart failure therefore needs to be reevaluated.
Key Words: mice, transgenic • nitric oxide • cardiac function • L-arginine
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