Published Online
on January 19, 2004

A more recent version of this article appeared on January 27, 2004

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Submitted on August 8, 2003
Revised on December 10, 2003
Accepted on December 11, 2003

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, and Gilles W. De Keulenaer MD, PhD^*

From the University of Antwerp, Antwerp, Belgium.

^* To whom correspondence should be addressed. E-mail: gilles.dekeulenaer{at}ua.ac.be.

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 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-1 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 -adrenergic stimulation and activates endothelial NO synthase in cardiomyocytes.

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

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