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

at their sites of biosynthesis or through renal or other indirect effects.
PGI 2
, the major arachidonate metabolite released from the vascular
endothelium, is derived primarily from COX-2 in humans (Catella-
Lawson et al., 1999; McAdam et al., 1999). PGI 2
generation and
release is regulated by shear stress and by both vasoconstrictor and
vasodilator autacoids. Deletion of the IP in mice augments vascular
proliferation, remodeling, atherogenesis, and hypertension, while
PGI synthase polymorphisms have been associated with essential
hypertension and myocardial infarction (Smyth and FitzGerald,
2009). PGI 2
limits pulmonary hypertension induced by hypoxia and
systemic hypertension induced by AngII and lowers pulmonary
resistance in patients with pulmonary hypertension.
Deficiency of EP 1
or EP 4
receptors reduces resting blood pressure
in male mice; EP 1
-receptor deficiency is associated with elevated
renin–angiotensin activity. Both EP 2
and EP 4
receptor–deficient animals
develop hypertension in response to a high-salt diet, reflecting
the importance of PGE 2
in maintenance of renal blood flow and salt
excretion. PGI 2
and PGE 2
are implicated in the hypotension associated
with septic shock. PGs also may play a role in the maintenance
of placental blood flow. Although conflicting data exist, it appears
that loss of mPGES-1 in mice is less likely than loss of COX-2 to
alter blood pressure (Smyth et al., 2009).
COX-2-derived PGE 2
, via the EP 4
receptor, maintains the
ductus arteriosus patent until birth, when reduced PGE 2
levels (a
consequence of increased PGE 2
metabolism) permit closure.
(Coggins et al., 2002). The tNSAIDs induce closure of a patent ductus
in neonates (see Chapter 34). Contrary to expectation, animals
lacking the EP 4
receptor die with a patent ductus during the perinatal
period (Table 33–1) because the mechanism for control of the
ductus in utero, and its remodeling at birth, is absent.
Endogenous biosynthesis of EETs is increased in human syndromes
of hypertension. An analog of 11,12-EET abrogated the
enhanced renal microvascular reactivity to AngII associated with
hypertension (Imig et al., 2001), and blood pressure is lower in mice
deficient in soluble EH (Sinal et al., 2000); these findings suggest
that EH enzyme may be a potential pharmacological target for hypertension.
Much indirect evidence suggests the existence of EET
receptors, although none has been cloned.
Inflammatory Vascular Disease. Studies with knockout mice
strongly implicate prostanoids in the development of atherogenesis
and abdominal aortic aneurism; both inflammatory cardiovascular
diseases (Smyth et al., 2009; Smyth and FitzGerald, 2009).
Suppression of TxA 2
biosynthesis, as well as antagonism or deletion
of the TP, retards atherogenesis in mice. Deletion of the FP
receptor reduces blood pressure and retards atherogenesis, coincident
with reduced renin. Conversely, PGI 2
appears atheroprotective
and also limits vascular proliferative and remodeling responses. In
humans, an arginine 212 to cysteine substitution in the fifth intracellular
loop of the IP, which disrupts IP signaling, co-segregated with
increased cardiovascular risk in a recent study (Arehart et al., 2008),
concordant with a role for this prostanoid in modifying human cardiovascular
disease.
The role of PGE 2
effects on inflammatory cardiovascular disease
is less clear. Deletion of mPGES-1 does not accelerate the
response to a thrombogenic stimulus in vivo in rodents (in contrast
to either selective inhibition of COX-2 or deletion of the IP (Cheng
et al., 2006b) but does retard atherogenesis in fat-fed hyperlipidemic
mice (Wang et al., 2006). It is unclear, however, whether this results
from loss of PGE 2
or because of concomitant elevations in PGI 2
biosynthesis. Deletion, or selective inhibition, of COX-2, but not
inhibition of COX-1, decreases abdominal aortic aneurism formation
in hyperlipidemic mice (King et al., 2006). Similar results were
seen in mPGES-1-deficient mice (Wang et al., 2008), although,
again, it is unclear to what extent rediversion to biosynthesis of other
prostanoids (e.g., PGI 2
) contributes.
There is growing evidence for a role of the LTs in cardiovascular
disease (Peters-Golden and Henderson, 2007). Although conflicting
data have been reported in animal studies, human genetic
studies have demonstrated a link between cardiovascular disease and
polymorphisms in the LT biosynthetic enzymes and FLAP.
Lung. A complex mixture of autacoids is released when sensitized
lung tissue is challenged by the appropriate antigen. COX-derived
bronchodilator (PGE 2
) and bronchoconstrictor (e.g., PGF 2α
, TxA 2
,
PGD 2
) substances are released. IP deletion in mice exaggerates features
of acute and chronic experimental asthma, including increased
bronchial hyperresponsiveness. Inhaled iloprost (a PGI 2
analog) suppresses
the cardinal features of asthma in mice via inhibition of airway
dendritic cell function.
Polymorphisms in the genes for PGD 2
synthase and the TP
receptor have been associated with asthma in humans. Deletion of
either DP 1
or DP 2
in mice suggests an important role of this prostanoid
in asthma (and in other allergic responses), although contradictory
findings in DP 2
-deficient mice suggest significant complexity in the
function of PGD 2
in airway inflammation (Pettipher et al., 2007).
The CysLTs probably dominate during allergic constriction of
the airway (Drazen, 1999). Deficiency of 5-LOX leads to reduced
influx of eosinophils in airways and attenuates bronchoconstriction.
Furthermore, unlike COX inhibitors and histaminergic antagonists,
CysLT-receptor antagonists and 5-LOX inhibitors are effective in
the treatment of human asthma (see “Inhibitors of Eicosanoid
Biosynthesis”). The relatively slow LT metabolism in lung contributes
to the long-lasting bronchoconstriction that follows challenge with antigen
and may be a factor in the high bronchial tone that is observed in
asthmatic patients in periods between acute attacks (see Chapter 36).
Kidney. Long-term use of all COX inhibitors is limited by the development
of hypertension, edema, and congestive heart failure in a significant
number of patients. PGE 2
, along with PGI 2
, apparently
derived from COX-2, plays a critical role in maintaining renal blood
flow and salt excretion, whereas there is some evidence that the COX-
1-derived vasoconstrictor TxA 2
may play a counterbalancing role.
Biosynthesis of PGE 2
and PGI 2
is increased by factors that reduce
renal blood flow (e.g., stimulation of sympathetic nerves; AngII).
Bartter’s syndrome is an autosomal recessive trait that is manifested
as hypokalemic metabolic alkalosis. The syndrome results
from inappropriate renal salt absorption caused primarily by dysfunctional
mutations in the Na + –K + –2Cl – co-transporter NKCC2, a
target of loop diuretics in the ascending thick limb of the loop of
Henle (Simon et al., 1996) (see Chapter 25). The syndrome also can
result from dysfunctional alterations in proteins whose activities can
limit NKCC2 function: the K + channel ROMK2 (Kir1.1) that recycles
K + into the tubular fluid; the basolateral membrane Cl – channel,
ClC–Kb; and Barttin, the integral membrane protein that forms
the α-subunit of the ClC–Kb heteromer (O’Shaughnessy and
Karet, 2004). The antenatal variant of Bartter’s syndrome, owing to
947
CHAPTER 33
LIPID-DERIVED AUTACOIDS: EICOSANOIDS AND PLATELET-ACTIVATING FACTOR