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

1060
A
Endothelial factors influencing
smooth muscle tone
B
Alterations in PAH
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Endothelium
VSM
membrane
ET-1 PGI 2 NO
Ca 2+ Ca 2+
Ca v 1.2
ET A
cAMP
[Ca 2+ ] i
Contraction
Proliferation
C
IP
cAMP
BALANCE
sGC
cGMP
Relaxation
Anti-proliferation
Drug effects in PAH
Ca 2+
Channel
antagonists
ET A
antagonists
Ca 2+
ET-1
PGI 2
analogs
Enhanced
Ca 2+ signaling
Contraction
Proliferation
ET-1 PGI 2
NO
Reduced cyclic
nucleotide signaling
Relaxation
Anti-proliferative
signaling
IMBALANCE
(favoring contraction and proliferation)
Exogenous
NO
Ca v 1.2 ET A IP
sGC
PDE5
inhibitors
[Ca 2+ ] i
More normal
Ca 2+ signaling
Contraction
Proliferation
cAMP cGMP 5'GMP
PDE5
More normal cyclic
nucleotide signaling
Relaxation
Anti-proliferation
RESTORED BALANCE
Figure 36–13. Interactions of endothelium and vascular smooth muscle in pulmonary artery hypertension (PAH). A. In normal pulmonary
artery, there is a balance between constrictor and relaxant influences that may be viewed as competition between Ca 2+ signaling pathways
and cyclic nucleotide signaling pathways in vascular smooth muscle (VSM). Endothelin (ET-1) binds to the ET A
receptor on VSM
cells and activates the G q
-PLC-IP 3
pathway to increase cytosolic Ca 2+ ; ET-1 may also couple to G i
to inhibit cyclic AMP (cAMP) production.
In depolarizing VSM cells, Ca 2+ may enter via the L-type Ca 2+ channel (Ca v
1.2). Endothelial cells also produce relaxant factors,
prostacyclin (PGI 2
) and NO. NO stimulates the soluble guanylyl cyclase (cGC), causing accumulation of cyclic GMP (cGMP) in VSM
cells; PGI 2
binds to the IP prostanoid receptor and stimulates the G s
-adenylyl cyclase pathway to enhance cAMP accumulation; elevation
of these cyclic nucleotides promotes VSM relaxation (see Chapter 3). B. In PAH, ET-1 production is enhanced, production of PGI 2
and NO is reduced, and the balance is shifted toward constriction and proliferation of vascular smooth muscle. C. In treating PAH, ET A
receptor antagonists can reduce the constrictor effects of ET-1, and Ca 2+ channel antagonists can further reduce Ca 2+ -dependent contraction.
Exogenous PGI 2
and NO can be supplied to promote vasodilation (relaxation of VSM); inhibition of PDE5 can enhance the relaxant
effect of NO by inhibiting the degradation of cGMP, thereby promoting intracellular accumulation of cGMP and relaxation of VSM.
Thus, these drugs can reduce Ca 2+ signaling and enhance cyclic nucleotide signaling, restoring the balance between the forces of contraction/proliferation
and relaxation/anti-proliferation. Remodeling and deposition of extracellular matrix by adjacent fibroblasts is influenced
positively and negatively by the same contractile and relaxant signaling pathways, respectively.