Biology Reference
In-Depth Information
failure (HF) by increasing expression of
b
-myosin heavy chain and other
genes belonging to the so-called fetal gene program of cardiac adverse rem-
odeling.
3
Carvedilol, a non-selective
b
AR blocker currently used with great
success in HF (see
Section 6
), is also an
a
1
AR antagonist, and antagonism of
the maladaptive cardiotoxic effects of cardiac
a
1
ARs might contribute to its
beneficial actions in HF treatment.
4
However, not all actions of cardiac
a
1
ARs are bad;
a
1
ARs can also stimulate “adaptive” or “physiological” car-
diac hypertrophy with no fibrosis or other manifestations of adverse remo-
deling, but rather with preservation or even augmentation of cardiac
function and stimulation of myocyte proliferation and ventricular muscle
wall thickening.
5,6
Unfortunately, very little data exist with respect to interactions of the
a
1
ARs with
b
arrs, regardless of whether these interactions mediate
a
1
AR
desensitization (i.e., termination of G protein signaling) or
b
arr-dependent
protein scaffolding/signaling. All of the available data are from
in vitro
studies
in heterologous cell systems (i.e., cell lines transfected with
a
1
AR subtypes)
with virtually nothing on
a
1
ARs and
b
arrs specifically in the cardiovascular
system.
7
Results from
in vitro
co-immunoprecipitation experiments and
b
arr
translocation assays have indicated that the agonist-induced interaction of
the
a
1A
AR with
b
arrs is much weaker than that of the
a
1B
AR.
8
The inter-
action of
b
arrs with the
a
1D
AR has not been directly explored, not even in
in vitro
systems, let alone in cardiovascular tissues.
7
Given that
a
1
ARs are
b
arr
substrates and play such important roles in cardiovascular regulation, includ-
ing stimulation of downstream effectors that can be activated by
b
arr-
dependent signaling cascades (e.g., mitogen-activated protein kinases,
MAPKs), it is evident that cardiovascular
b
arr biology with relation to
a
1
ARs has the potential for providing invaluable new information in the
future.
2.2.
a
2
-Adrenergic receptors
2.2.1 Cardiovascular
a
2
ARs and
b
arrs as desensitizers
Of the three pharmacological
a
2
AR subtypes (
a
2A
,
a
2B
,
a
2C
), the
a
2B
AR is
the predominant one expressed in smooth muscle cells of various vascular
beds, wherein, like the
a
1
AR subtypes, it mediates vasoconstriction and
can raise blood pressure. This distinguishes it from the other
a
2
AR subtype
counterparts, which are present in the central sympathetic nervous system,
that lower blood pressure by decreasing central sympathetic outflow.
9
Therefore, prolongation of centrally acting “sympatholytic”
a
2
AR signal-
ing/function, for example, inhibition of
b
arr desensitizing actions on these
Search WWH ::
Custom Search