Circulation. 2001;104:3097-3102
Published online before print November 19, 2001, doi: 10.1161/hc5001.101966
Published online before print November 19, 2001, doi: 10.1161/hc5001.101966
(Circulation. 2001;104:3097.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Myocardial Contractile Function and Heart Rate in Mice With Myocyte-Specific Overexpression of Endothelial Nitric Oxide Synthase
From the Institut für Pharmakologie und Toxikologie (F.B., P.A., G.W., B.M.), and the Institut für Molekularbiologie, Biochemie und Mikrobiologie (R.Z.), Karl-Franzens-Universität Graz, Graz, Austria
Correspondence to Friedrich Brunner, Institut für Pharmakologie und Toxikologie, Karl-Franzens-Universität Graz, Universitätsplatz 2, A-8010 Graz, Austria. E-mail friedrich.brunner{at}kfunigraz.ac.at
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 ß-adrenergic stimulation with norepinephrine, and these responses were identical in WT and TG hearts. Finally, resting systolic intracellular calcium (Ca2+i) tended to be lower in TG than in WT hearts, and the beat-to-beat responsiveness to Ca2+i was reduced in hearts with eNOS overexpression.
Conclusions— High levels of endogenous myocyte-derived NO blunt myofilament Ca2+ 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.
Key Words: nitric oxide synthase • contractility • acetylcholine • norepinephrine • calcium
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