Increased sympathetic nerve activity to the myocardium is a central feature
in patients with heart failure. Norepinephrine, the primary transmitter of
the sympathetic nervous system, signals via binding to alpha- and beta-adr
energic receptors (AR) that are coupled to G-proteins. Pharmacologic studie
s of cardiac myocytes in vitro demonstrate that P-AR can stimulate apoptosi
s. Likewise, in transgenic mice overexpression of beta(1)-AR or Gas is asso
ciated with myocyte apoptosis and the development of dilated cardiomyopathy
. Whereas beta(1)-AR stimulate apoptosis in vitro and in vivo, beta(2)-AR m
ay either stimulate or inhibit apoptosis and myocardial failure depending o
n the level of expression. Receptors coupling to Gi and Gq may also be able
to mediate or modulate apoptosis and the development of myocardial failure
, suggesting the potential for interactions between the beta-AR system and
numerous remodeling stimuli that act through Gi or Gq signaling pathways. I
t appears likely that the mitogen-activated protein kinase superfamily play
s a key role in mediating the actions of adrenergic pathways on myocyte apo
ptosis. These observations suggest that the adrenergic nervous system plays
an important role in the regulation of myocyte apoptosis, and may thus con
tribute to the development of myocardial failure. (C) 2000 Elsevier Science
B.V. All rights Reserved.