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(Circulation. 2004;109:324-326.)
© 2004 American Heart Association, Inc.

Brief Rapid Communications

Neuregulin-1 Induces a Negative Inotropic Effect in Cardiac Muscle

Role of Nitric Oxide Synthase

Katrien Lemmens, MD; Paul Fransen, PhD; Stanislas U. Sys, MD, PhD; Dirk L. Brutsaert, MD, PhD; Gilles W. De Keulenaer, MD, PhD

From the University of Antwerp, Antwerp, Belgium.

Correspondence to Gilles W. De Keulenaer, MD, PhD, Laboratory of Physiology, University of Antwerp, Groenenborgerlaan 171, Building V, 6th Floor, 2020 Antwerp, Belgium. E-mail gilles.dekeulenaer{at}ua.ac.be

Received August 8, 2003; de novo received October 8, 2003; revision received December 10, 2003; accepted December 11, 2003.

Background— Deficient cardiac neuregulin/ErbB signaling increases susceptibility to heart failure. In this study, we examined the effects of neuregulin-1 (NRG-1) on myocardial contractility.

Methods and Results— NRG-1 ( and ß isoforms) induced a negative inotropic effect in isolated rabbit papillary muscles and a rightward shift of the dose-response curve to isoproterenol. Both effects were attenuated by L-NMMA, which suggests a role for NO synthase. In cultured rat cardiomyocytes, NRG-1ß enhanced nitrite production and resulted in phosphorylation of endothelial NO synthase and the serine/threonine kinase Akt.

Conclusions— NRG-1 has negative inotropic effects that are preserved during ß-adrenergic stimulation and activates endothelial NO synthase in cardiomyocytes.

Key Words: neuregulin • nitric oxide synthase • endothelium • contractility • heart failure

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