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(Circulation. 2004;110:713-717.)
© 2004 American Heart Association, Inc.

Original Articles

Neuregulins Regulate Cardiac Parasympathetic Activity

Muscarinic Modulation of ß-Adrenergic Activity in Myocytes From Mice With Neuregulin-1 Gene Deletion

Katashi Okoshi, MD; Masaharu Nakayama, MD; Xinhua Yan, MD; Marina P. Okoshi, MD; Adam J.T. Schuldt, BA; Mark A. Marchionni, PhD; Beverly H. Lorell, MD

From the Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (K.O., M.N., X.Y., M.P.O., A.J.T.S., B.H.L.), and NRG Biotech, Arlington, Mass (M.A.M.).

Correspondence to Beverly H. Lorell, MD, Cardiovascular Division–East Campus, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Room RW453, Boston, MA 02215. E-mail blorell{at}bidmc.harvard.edu

Received October 22, 2003; de novo received February 17, 2004; accepted April 26, 2004.

Background— Neuregulins are required for maintenance of acetylcholine receptor–inducing activity of nicotinic receptors in neurons and skeletal muscle, but effects of neuregulins on muscarinic receptors are not known. In the normal heart, parasympathetic activation counterbalances ß-adrenergic activation. To test the hypothesis that neuregulins modify parasympathetic function in the heart, we studied cardiomyocytes from mice heterozygous for neuregulin-1 gene deletion (NRG-1^+/–) and examined the effects of ß-adrenergic stimulation on contractility in the presence and absence of the muscarinic agonist carbachol.

Methods and Results— We evaluated contraction and intracellular Ca²⁺ transients ([Ca²⁺]_i) in left ventricular (LV) myocytes loaded with Fluo-3 from NRG-1^+/– and wild-type (WT) mice. Under baseline conditions (0.5 Hz, 1.5 mmol/L [Ca²⁺]_o, 25°C), characteristics of myocyte contraction/relengthening and systolic/diastolic [Ca²⁺]_i were not different between WT and NRG-1^+/– mice. The steady-state increases in fractional shortening (FS) and peak-systolic [Ca²⁺]_i in response to isoproterenol were similar in both groups. In WT myocytes stimulated with isoproterenol, carbachol decreased FS, peak-systolic [Ca²⁺]_i, and cAMP levels. In NRG-1^+/– myocytes, carbachol did not attenuate either FS or peak-systolic [Ca²⁺]_i, associated with the failure to decrease cAMP levels. Investigation of muscarinic receptor signaling showed no difference of LV protein levels of muscarinic M₂ receptors or G protein G_i1,2, G_i3, and G_o subunits.

Conclusions— Cardiomyocytes deficient in neuregulin signaling are unable to adequately counterbalance ß-adrenergic activation by inhibitory parasympathetic activity. This mechanism may contribute to the known increased risk of heart failure in injured human hearts when neuregulin signaling is suppressed.

Key Words: acetylcholine • neuregulins • calcium • contractility • myocytes

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