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

receptors as products of oncogenes that transform otherwise normal
cells into malignant cells. Virtually any type of signaling system may
have oncogenic potential.
PHARMACODYNAMIC INTERACTIONS
IN A MULTICELLULAR CONTEXT
It is instructive to examine the pharmacodynamic interactions
of physiological ligands and drugs that can occur
in the context of a pathophysiological setting. Consider
the vascular wall of an arteriole (Figure 3–14). Several
cell types interact at this site, including vascular smooth
muscle cells (SMCs), endothelial cells (ECs), platelets,
and post-ganglionic sympathetic neurons. A variety of
physiological receptors and ligands are represented,
including ligands that cause SMCs to contract
(angiotensin II [AngII], norepinephrine [NE]) and relax
(nitric oxide [NO], B-type natriuretic peptide [BNP],
and epinephrine), as well as ligands that alter SMC gene
expression (platelet-derived growth factor [PDGF],
AngII, NE, and eicosanoids). The intracellular second
messengers Ca 2+ , cAMP, and cGMP are also shown.
AngII has both acute and chronic effects on SMC.
Interaction of AngII with AT 1
receptors (AT 1
-R) causes
the formation of the second messenger IP 3
through the
Platelet
ACh
PDGF AngII Epinephrine
BNP AngII
M-R
action of the AT 1
-R with the G q
-PLC-IP 3
pathway. IP 3
causes the release of Ca 2+ from the endoplasmic reticulum;
the Ca 2+ binds and activates calmodulin and its
target protein, myosin light chain kinase (MLCK). The
activation of MLCK results in the phosphorylation of
myosin, leading to smooth muscle cell contraction.
Activation of the sympathetic nervous system also regulates
SMC tone through release of NE from postganglionic
sympathetic neurons impinging on SMCs.
NE binds α 1
adrenergic receptors that couple to the G q
-
PLC-IP 3
pathway, causing an increase in intracellular
Ca 2+ and, as a result, contraction, an effect that is additive
to that of AngII. The contraction of SMCs is
opposed by several physiological mediators that promote
relaxation, including NO, BNP, and epinephrine.
NO is formed in ECs by the action of two NO synthase
enzymes, eNOS and iNOS. The NO formed in ECs diffuses
into SMCs, and activates the soluble form of
guanylate cyclase (sGC), which catalyzes the formation
of cyclic GMP from GTP. The increase in cyclic
GMP activates PKG, which phosphorylates protein
substrates in SMCs that reduce intracellular concentrations
of Ca 2+ by several different mechanisms including
reducing entry of extracellular Ca 2+ through L-type
voltage-gated Ca 2+ channels. Intracellular concentrations
Vascular lumen
69
CHAPTER 3
PHARMACODYNAMICS: MOLECULAR MECHANISMS OF DRUG ACTION
Endothelial cells
PDGF-R
AT 1 -R
β 2 -R
NO
BNP-R
AT 1 -R
sGC
Eicosanoids
PPARγ
CREB
cAMP
cGMP
SR
Ca 2+
IP 3
α 1 -R
NE
Adrenergic
nerve
Altered
gene
expression
Relaxation
Contraction
Ca 2+
L-type Ca 2+ channel
Vascular smooth muscle cell
Figure 3–14. Interaction of multiple signaling systems regulating vascular smooth muscle cells. The membrane receptors and channels
are sensitive to pharmacological antagonists. See text for explanation of signaling and contractile pathways and abbreviations.