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1D-Adrenergic Receptors and Mitogen-Activated
Protein Kinase Mediate Increased Protein Synthesis by Arterial
Smooth Muscle
Department of Physiology, University of North Carolina, Chapel
Hill, North Carolina 27599-7545
Catecholamines may influence vascular smooth muscle cell (SMC) growth
and vascular hypertrophic diseases. We previously demonstrated that
stimulation of 
1-adrenoceptors (AR) causes hypertrophy
of vascular SMCs in vitro and in situ.
Here, we used adult rat aorta SMCs that express 1D- and
1B-ARs (but not 1A-ARs) in
vitro to examine the mechanisms and 1-AR
subtypes involved. Norepinephrine (NE) increased protein synthesis and
content in a time- and dose-dependent manner. To identify the
responsible 1-AR subtype, we first documented the
selectivity of two 1-AR subtype antagonists, BMY 7378 (1D-AR antagonist) and chloroethylclonidine (CEC;
1B-AR antagonist), using Rat-1 fibroblasts stably
transfected with the three different rodent 1-AR cDNAs.
NE dose-dependently increased protein synthesis in each cell line. In
1D fibroblasts, BMY 7378 inhibited growth and protected
1D-ARs from CEC alkylation while having little blocking
or protecting effect on the growth induced by stimulation of
fibroblasts that express 1A- or 1B-ARs.
In rat aorta SMCs, pretreatment with CEC in the presence of BMY 7378 to
protect 1D-ARs had no effect on NE-induced protein
synthesis. BMY 7378 inhibited the SMC growth response with a
pKb of 8.4. NE caused rapid and
transient p42-p44 mitogen-activated protein kinase (MAPK) activation
that was 1D-AR dependent. Furthermore, NE caused
tyrosine phosphorylation of multiple cellular proteins, phosphorylation of Raf-1, and stimulation of c-fos mRNA expression in
aorta SMCs. The selective MAPK kinase inhibitor PD 98059 inhibited
NE-induced protein synthesis and MAPK activation with IC50
values of 2.3 and 1.6 µM, respectively. These data
demonstrate that SMC growth induced by NE is mediated by
1D-ARs that couple to activation of the MAPK cascade.
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