DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

64 from the complex allowing the p50/p65 heterodimer of the complex
to translocate to the nucleus and activate the transcription of inflammatory
genes (Ghosh and Hayden, 2008; Hayden and Ghosh, 2008;
Kataoka, 2009). While there currently are no drugs that interdict the
cytoplasmic portions of the TNF-α signaling pathway, humanized
monoclonal antibodies to TNF-α itself, such as infiximab and adalimumab,
are important for the treatment of rheumatoid arthritis and
Crohn’s disease (Chapters 35 and 47).
SECTION I
GENERAL PRINCIPLES
Receptors That Stimulate Synthesis of
Cyclic GMP
The signaling pathways that regulate the synthesis of
cyclic GMP in cells include hormonal regulation of
transmembrane guanylate cyclases such as the atrial
natriuretic peptide receptor (ANP) and the activation of
soluble forms of guanylate cyclase by nitric oxide (NO).
The downstream effects of cyclic GMP are carried out
by multiple isoforms of PKG, cyclic GMP-gated ion
channels, and cyclic GMP-modulated phosphodiesterases
that degrade cyclic AMP (described later).
Natriuretic Peptide Receptors. The class of membrane
receptors with intrinsic enzymatic activity includes the
receptors for three small peptide ligands released from
cells in cardiac tissues and the vascular system. These
peptides are atrial natriuretic peptide (ANP), which is
released from atrial storage granules following expansion
of intravascular volume or stimulation with pressor
hormones; brain natriuretic peptide (BNP), which
(in spite of its name) is synthesized and released in
large amounts from ventricular tissue in response to
volume overload; and C-type natriuretic peptide (CNP),
which is synthesized in the brain and endothelial cells.
Like BNP, CNP is not stored in granules; rather, its synthesis
and release are increased by growth factors and
sheer stress on vascular endothelial cells (Potter et al.,
2009). The major physiological effects of these hormones
are to decrease blood pressure (ANP, BNP), to
reduce cardiac hypertrophy and fibrosis (BNP), and to
stimulate long bone growth (CNP).
The transmembrane receptors for ANP, BNP, and
CNP are ligand-activated guanylate cyclases. The ANP
and BNP receptors contain a ~450 amino acid extracellular
domain that binds the peptide, a short 20 amino
acid transmembrane domain, and large intracellular
domains that contain a kinase homology region, a
dimerization domain, and a C-terminal guanylate
cyclase domain. Phosphorylation of serine residues in
the kinase domain is important for activity; dephosphorylation
of these residues leads to desensitization of the
receptor. Ligand binding brings the juxtamembrane
regions together and stimulates guanylate cyclase activity
(Figure 3–11).
The ANP receptor (NPR-A) is the molecule that responds to
ANP and BNP. The protein is widely expressed and prominent in
kidney, lung, adipose, and cardiac and vascular smooth muscle cells.
ANP and BNP play a role in maintaining the normal state of the cardiovascular
system as NPR-A knockout mice have hypertension and
cardiac hypertrophy. A synthetic BNP agonist, nesiritide, is used for
treatment of acute decompensated heart failure (Chapter 28). The
NPR-B receptor responds to CNP and has a physical structure similar
to the NPR-A receptor. It is also widely expressed but prominent
in bone, brain, kidney, lung, liver, and cardiac and vascular
smooth muscle. A role for CNP in bone is suggested by the observation
that NPR-B knockout mice exhibit both dwarfism and cardiac
hypertrophy. The natriuretic peptide C receptor (NPR-C) has
an extracellular domain similar to those of NPR-A and NPR-B but
does not contain the intracellular kinase or guanylate cyclase
domains. It has no enzymatic activity and is thought to function as
a clearance receptor, removing excess natriuretic peptide from the
circulation (Potter et al., 2009).
NO Synthase and Soluble Guanylate Cyclase. Nitric
oxide (NO) is a unique signal, a very labile gas produced
locally in cells by the enzyme nitric oxide synthase
(NOS); the resulting NO is able to markedly
stimulate the soluble form of guanylate cyclase to
produce cyclic GMP. There are three forms of nitric
oxide synthase, neuronal NOS (nNOS or NOS1),
endothelial NOS (eNOS or NOS3), and inducible NOS
(iNOS or NOS2). All three forms of this enzyme are
widely expressed but are especially important in the cardiovascular
system, where they are found in myocytes,
vascular smooth muscle cells, endothelial cells,
hematopoietic cells, and platelets.
NOS produces NO by catalyzing the oxidation of the guanido
nitrogen of L-arginine, producing L-citrulline and NO. The enzymes
require co-factors including tetrahydrobioptern and calmodulin. The
nNOS and eNOS forms of the enzyme are markedly activated by
Ca 2+ /calmodulin; the inducible form is less sensitive to Ca 2+ but the
level of iNOS protein in cells can be increased over 1000-fold by
inflammatory stimuli such as endotoxin, TNF-α, interleukin-1β and
interferon-γ. The ability of Ca 2+ to activate eNOS and nNOS is
important in certain cells where neurotransmitters that open Ca 2+
channels or activate PLC can relax smooth muscle. An example is
the ability of ACh released by the parasympathetic nervous system
to relax sphincters. Soluble guanylate cyclase is a heterodimer composed
of α and β subunits. The N-terminal end of the molecule contains
a protoporphyrin-IX heme domain. NO binds to this domain at
low nM concentrations and produces a 200- to 400-fold increase in
the V max
of guanylate cyclase, leading to a marked elevation of cyclic
GMP in the cell (Tsai and Kass, 2009).
The cellular effects of cyclic GMP on the vascular system are
mediated by a number of mechanisms, but especially by PKG. For
example, in vascular smooth muscle, activation of PKG leads to
vasodilation by: