Neuregulin-1 Induces a Negative Inotropic Effect in Cardiac Muscle

Abstract

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