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

948 dysfunctional ROMK2, also is known as hyperprostaglandin E syndrome.
The elevated PGE 2
may exacerbate the symptoms of salt and
water loss. The relationship between dysfunctional ROMK2 and elevated
PGE 2
synthesis is not clear. However, in patients with antenatal
Bartter’s syndrome, inhibition of COX-2 ameliorates many of the
clinical symptoms (Nüsing et al., 2001).
Inflammatory and Immune Responses. PGs and LTs are synthesized
in response to a host of stimuli that elicit inflammatory and
immune responses, and contribute significantly to inflammation and
immunity (Tilley et al., 2001; Brink et al., 2003; Kim and Luster,
2007). Prostanoids generally promote acute inflammation, although
there are some exceptions, such as the inhibitory actions of PGE 2
on
mast cell activation (see “Inflammation and Immunity”). Data from
animals deficient in either COX-1 or COX-2 yield conflicting results
depending on the inflammatory model used, perhaps reflecting the
contribution of both isozymes to inflammation. Deletion of mPGES
markedly reduced inflammation in several mouse models.
LTs are potent mediators of inflammation. Deletion of either
5-LOX or FLAP reduces inflammatory responses. Generation of
BLT 1
-deficient mice confirms the role of LTB 4
in chemotaxis, adhesion,
and recruitment of leukocytes to inflamed tissues (Toda et al.,
2002). Increased vascular permeability resulting from innate and
adaptive immune challenges is offset in mice deficient in CysLT 1
or
LTC 4
synthase (Kanaoka and Boyce, 2004) (Table 33–1). Deletion
either of LTC 4
synthase (and thus loss of CysLT biosynthesis) or
CysLT 2
reduced chronic pulmonary inflammation and fibrosis in
response to bleomycin. In contrast, absence of CysLT 1
led to an exaggerated
response. These findings demonstrate a role for CysLT 2
in
promoting, and an unexpected role for CysLT 1
in counteracting,
chronic inflammation.
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Heart. Studies suggest a role for COX-2 in cardiac function (Smyth
et al., 2009). PGI 2
and PGE 2
, acting on the IP or the EP 3
, respectively
(Dowd et al., 2001; Shinmura et al., 2005), protect against
oxidative injury in cardiac tissue. IP deletion augments myocardial
ischemia/reperfusion injury and both mPGES-1 deletion (Degousee
et al., 2008) and cardiomyocyte specific deletion of the EP 4
(Qian
et al., 2008) exacerbate the decline in cardiac function after experimental
myocardial infarction. COX-2-derived TxA 2
contributed to
oxidant stress, isoprostane generation, and activation of the TP, and
also possibly the FP, to increase cardiomyocyte apoptosis and fibrosis
in a model of heart failure (Zhang et al., 2003). Selective deletion
of COX-2 in cardiomyocytes results in mild heart failure and a predisposition
to arrhythmogenesis.
Reproduction and Parturition. Studies with knockout mice confirm
a role for PGs in reproduction and parturition (Smyth and
FitzGerald, 2009). COX-1-derived PGF 2α
appears important for luteolysis,
consistent with delayed parturition in mice deficient in
COX-1. Subsequent upregulation of COX-2 generates prostanoids,
including PGF 2α
and TxA 2
, that are important in the final stages of
parturition. Mice lacking both COX-1 and oxytocin undergo normal
parturition, demonstrating the critical interplay between PGF 2α
and
oxytocin in onset of labor. EP 2
receptor–deficient mice demonstrate
a preimplantation defect (Table 33–1), which likely underlies some
of the breeding difficulties seen in COX-2 knockouts.
Cancer. Pharmacological inhibition or genetic deletion of COX-2
restrains tumor formation in models of colon, breast, lung, and other
cancers. Large human epidemiological studies report that the incidental
use of NSAIDs is associated with significant reductions in
relative risk for developing these and other cancers (Harris et al.,
2005). PGE 2
has been implicated as the primary pro-oncogenic
prostanoid in multiple studies. The pro- and anti-oncogenic roles of
other prostanoids remain under investigation, with TxA 2
emerging as
another likely COX-2-derived pro-carcinogenic mediator. Studies in
mice lacking EP 1
, EP 2
, and EP 4
reduce disease in multiple carcinogenesis
models. EP 3
, in contrast, may even play a protective role in
some cancers. Three randomized controlled trials of COX-2
inhibitors reported a significant reduction in the reoccurrence of adenomas
in patients receiving either celecoxib or rofecoxib compared
to placebo (Bertagnolli, 2007), while polymorphisms in COX-2 have
been associated with an increased risk of colon and other cancers. In
mouse mammary tissue, COX-2 is pro-oncogenic (Liu et al., 2001),
whereas aspirin use is associated with a reduced risk of breast cancer
in women, especially for hormone receptor–positive tumors
(Terry et al., 2004). Despite the emphasis on COX-2, studies support
a role for both COX enzymes in pro-oncogenic processes, and it
remains untested whether selective COX-2 inhibitors will prove
superior to nonselective NSAIDs for the prevention or treatment of
human cancer. The CysLT and LTB 4
receptors also are implicated in
cancer, raising interest in the use of LT inhibitors/antagonists in
chemoprevention/therapy.
Pharmacological Effects
Cardiovascular System. Prostanoids do not circulate and
thus do not directly impact systemic vascular tone.
They may, however, modulate local vascular tone at
the site of their formation and affect systemic blood
pressure through their renal actions, including changes
of tone of the efferent arteriole. In most vascular beds,
PGE 2
, PGI 2
, and PGD 2
elicit vasodilation and a drop
in blood pressure (Smyth and FitzGerald, 2009). PGE 2
can cause vasoconstriction through activation of the
EP 1
and EP 3
. Infusion of PGD 2
in humans results in
flushing, nasal stuffiness, and hypotension. Local subcutaneous
release of PGD 2
contributes to dilation of
the vasculature in the skin, which causes facial flushing
associated with niacin treatment in humans
(Cheng et al., 2006a). Subsequent formation of F-ring
metabolites from PGD 2
may result in hypertension.
PGI 2
relaxes vascular smooth muscle, causing
hypotension and reflex tachycardia on intravenous
administration. Responses to PGF 2α
vary with species
and vascular bed; it is a potent constrictor of both pulmonary
arteries and veins in humans. Blood pressure is
increased by PGF 2α
in some experimental animals,
owing to venoconstriction; however, in humans, PGF 2α
does not alter blood pressure. TxA 2
is a potent vasoconstrictor.
It contracts vascular smooth muscle in
vitro and is a vasoconstrictor in the whole animal and
in isolated vascular beds.