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

Cardiac output generally is increased by infusion of PGs of
the E and F series. Weak, direct inotropic effects have been noted in
various isolated preparations. In the intact animal, however,
increased force of contraction and increased heart rate are, in large
measure, a reflex consequence of a fall in total peripheral resistance.
Animal studies suggest direct cardioprotective effects of PGI 2
and
PGE 2
(Smyth et al., 2009).
LTC 4
and LTD 4
can constrict or relax isolated vascular
smooth muscle preparations, depending on the concentrations used
and the vascular bed (Brink et al., 2003). Hypotension in humans
may result partly from a decrease in intravascular volume and also
from decreased cardiac contractility secondary to a marked LTinduced
reduction in coronary blood flow. Although LTC 4
and LTD 4
have little effect on most large arteries or veins, coronary arteries
and distal segments of the pulmonary artery are contracted by
nanomolar concentrations of these agents. The renal vasculature is
resistant to this constrictor action, but the mesenteric vasculature is
not. LTC 4
and LTD 4
act in the microvasculature to increase permeability
of postcapillary venules; they are approximately 1,000-fold
more potent than histamine in this regard. At higher concentrations,
LTC 4
and LTD 4
can constrict arterioles and reduce exudation of
plasma. Vascular smooth muscle proliferation can be promoted by
12S-HETE and 20-HETE.
EETs cause vasodilation in a number of vascular beds by activating
the large conductance Ca 2+ -activated K + channels of smooth
muscle cells, thereby hyperpolarizing the smooth muscle and causing
relaxation. EETs likely also function as endothelium-derived hyperpolarizing
factors (EDHFs), particularly in the coronary circulation
(Campbell and Falck, 2007). In contrast to EETs, 20-HETE inhibits
large conductance Ca 2+ -activated K + channels, resulting in depolarization
of the vascular smooth muscle cell, Ca 2+ entry, and potent
vasoconstriction (Kroetz and Xu, 2005). Evidence supports the role
of 20-HETE in the regulation of vascular tone, particularly in renal
autoregulation.
Isoprostanes usually are vasoconstrictors, although there are
examples of vasodilation in preconstricted vessels.
Platelets. Low concentrations of PGE 2,
via the EP 3
,
enhance platelet aggregation. In contrast, higher concentrations
of PGE 2
, acting via the IP or possibly the G s
-
coupled EP 2
or EP 4
, inhibit platelet aggregation (Smyth
et al., 2009). Both PGI 2
and PGD 2
inhibit the aggregation
of human platelets in vitro, through cyclic AMP–dependent
deactivation of myosin light-chain kinase.
Mature platelets express only COX-1. Megakaryocytes and
immature platelet forms, released in clinical conditions of accelerated
platelet turnover, also express COX-2 (Rocca et al., 2002), but
its role in platelet development and function has yet to be elucidated.
TxA 2
, the major product of COX-1 in platelets, induces platelet
shape change, through G 12
/G 13
-mediated Rho/Rho-kinase-dependent
regulation of myosin light-chain phosphorylation, and aggregation
through G q
-dependent activation of PKC. Perhaps more importantly,
TxA 2
amplifies the signal for other, more potent platelet agonists,
such as thrombin and ADP (FitzGerald, 1991). The actions of TxA 2
on platelets are restrained by its short t 1/2
(~30 seconds), by rapid TP
desensitization, and by endogenous inhibitors of platelet function,
including NO and PGI 2
, which inhibits platelet aggregation by all
recognized agonists. The biological importance of 12-HETE formation
is poorly understood, although deletion of the platelet 12-LOX
augments ADP-induced platelet aggregation and AA-induced sudden
death in mice. Some isoprostanes increase the response of platelets
to pro-aggregatory agonists in vitro.
Inflammation and Immunity. Eicosanoids play a major
role in the inflammatory and immune responses, as
reflected by the clinical usefulness of the NSAIDs.
While LTs generally are pro-inflammatory and lipoxins
anti-inflammatory, prostanoids can exert both kinds of
activity. A more complete description of inflammation
is outlined in Chapter 34.
COX-2 is the major source of prostanoids formed during and
after an inflammatory response, although COX-1 also contributes.
PGE 2
and PGI 2
are the predominant pro-inflammatory prostanoids,
as a result of increased vascular permeability and blood flow in the
inflamed region. TxA 2
can increase platelet–leukocyte interaction.
Prostanoids, especially PGD 2
, also contribute to resolution of inflammation.
PGs generally inhibit lymphocyte function and proliferation,
suppressing the immune response (Rocca et al., 2002). PGE 2
depresses the humoral antibody response by inhibiting the differentiation
of B lymphocytes into antibody-secreting plasma cells. PGE 2
acts on T lymphocytes to inhibit mitogen-stimulated proliferation
and lymphokine release by sensitized cells. PGE 2
and TxA 2
also may
play a role in T lymphocyte development by regulating apoptosis of
immature thymocytes (Tilley et al., 2001). PGD 2
, a major product of
mast cells, is a potent leukocyte chemoattractant (Pettipher et al.,
2007), primarily through the DP 2
. Activation of the DP 2
promotes
chemotaxis and activation of T H
2 lymphocytes, eosinophils, and
basophils. The PGD 2
degradation product, 15d-PGJ 2
, also may activate
eosinophils via the DP 2
. PDG 2
-mediated polarization of T cells
to the T H
2 phenotype is DP 1
-mediated. A counterregulatory role for
DP 1
in leukocyte activation has been proposed, although complementary
functions for the two receptors have been reported. The precise
interplay between DP 1
and DP 2
in vivo remains to be clarified.
LTB 4
is a potent activator and chemotactic agent for neutrophils,
T lymphocytes, eosinophils, monocytes, dendritic cells, and
possibly also mast cells (Kim and Luster, 2007). These effects are
primarily BLT 1
receptor-mediated and, although BLT 2
expression has
been reported in eosinophils, mast cells, and dendritic cells, its contribution
to LBT 4
function is unclear. LTB 4
stimulates the aggregation
of eosinophils and promotes degranulation and the generation of
superoxide. LTB 4
promotes adhesion of neutrophils to vascular
endothelial cells and their transendothelial migration and stimulates
synthesis of pro-inflammatory cytokines from macrophages and lymphocytes.
Mast cell–generated LTB 4
also may contribute significantly
to T lymphocyte migration.
The CysLTs are chemotaxins for eosinophils and monocytes
through activation of the CysLT 1
receptor. They also induce cytokine
generation in eosinophils, mast cells, and dendritic cells. A distinct
set of cytokines are produced through activation of mast cell CysLT 1
and CysLT 2
. At higher concentrations, these LTs also promote
eosinophil adherence, degranulation, cytokine or chemokine release,
and oxygen radical formation. In addition, CysLTs contribute to
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CHAPTER 33
LIPID-DERIVED AUTACOIDS: EICOSANOIDS AND PLATELET-ACTIVATING FACTOR