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

Stomach. In addition to contracting the fundus of the stomach, PAF
is the most potent known ulcerogen. When given intravenously, it
causes hemorrhagic erosions of the gastric mucosa that extend into
the submucosa.
Kidney. When infused intrarenally in animals, PAF decreases renal
blood flow, glomerular filtration rate, urine volume, and excretion
of Na + without changes in systemic hemodynamics (Lopez-Novoa,
1999). These effects are the result of a direct action on the renal circulation.
PAF exerts a receptor-mediated biphasic effect on afferent
arterioles, dilating them at low concentrations and constricting them
at higher concentrations. The vasoconstrictor effect appears to be
mediated, at least in part, by COX products, whereas vasodilation is
a consequence of the stimulation of NO production by endothelium.
Other. PAF receptor-overexpressing mice spontaneously develop
melanocyte tumors. PAF, a potent mediator of angiogenesis, also has
been implicated in breast and prostate cancer. PAF-AH deficiency
has been associated with small increases in a range of cardiovascular
and thrombotic diseases in some human populations (Stafforini,
2009). Administration of PAF-AH reduces injury-induced neointima
formation and atherogenesis in genetically prone mice, suggesting a
role for PAF in inflammatory cardiovascular disease.
Receptor Antagonists. Several experimental PAFreceptor
antagonists exist that selectively inhibit the
actions of PAF in vivo and in vitro. One would
expect a PAF-receptor antagonist to be a potent antiinflammatory
agent that might be useful in the therapy
of disorders such as asthma, sepsis, and other diseases
in which PAF is postulated to play a role. However,
trials in humans have been disappointing, and the clinical
efficacy of PAF antagonists has yet to be realized.
Plasma PAF-AH activity modulates the acute and
chronic inflammatory response in animal models,
indicating that it may provide an alternative inflammatory
drug target. However, humans that are
homozygous for a mutant PAF-AH, leading to undetectable
levels of plasma PAF-AH, do not display rampant
inflammation (McIntyre et al., 2009), and thus
far, PAF-AH has not been translated into a meaningful
therapeutic approach.
BIBLIOGRAPHY
Arehart E, Stitham J, Asselbergs FW, et al. Acceleration of cardiovascular
disease by a dysfunctional prostacyclin receptor
mutation: Potential implications for cyclooxygenase-2 inhibition.
Circ Res, 2008, 102:986–993.
Audoly LP, Rocca B, Fabre JE, et al. Cardiovascular responses
to the isoprostanes iPF(2alpha)-III and iPE(2)-III are mediated
via the thromboxane A(2) receptor in vivo. Circulation, 2000,
101:2833–2840.
Austin SC, Funk CD. Insight into prostaglandin, leukotriene, and
other eicosanoid functions using mice with targeted gene disruptions.
Prostaglandins Other Lipid Mediat, 1999, 58:
231–252.
Bell-Parikh LC, Ide T, Lawson JA, et al. Biosynthesis of 15-
deoxy-delta12,14-PGJ2 and the ligation of PPARgamma. J Clin
Invest, 2003, 112:945–955.
Bertagnolli MM. Chemoprevention of colorectal cancer with
cyclooxygenase-2 inhibitors: Two steps forward, one step
back. Lancet Oncol, 2007, 8:439–443.
Bisogno T. Endogenous cannabinoids: Structure and metabolism.
J Neuroendocrinol, 2008, 20(suppl):1–9.
Brame CJ, Boutaud O, Davies SS, et al. Modification of proteins
by isoketal-containing oxidized phospholipids. J Biol Chem,
2004, 279:13447–13451.
Brash AR. Lipoxygenases: Occurrence, functions, catalysis, and
acquisition of substrate. J Biol Chem, 1999, 274:23679–23682.
Brink C, Dahlen SE, Drazen J, et al. International Union of
Pharmacology XXXVII. Nomenclature for leukotriene and
lipoxin receptors. Pharmacol Rev, 2003, 55:195–227.
Campbell WB, Falck JR. Arachidonic acid metabolites as
endothelium-derived hyperpolarizing factors. Hypertension,
2007, 49:590–596.
Capdevila JH, Falck JR. Biochemical and molecular properties
of the cytochrome P450 arachidonic acid monooxygenases.
Prostaglandins Other Lipid Mediat, 2002, 68–69:325–344.
Catella-Lawson F, McAdam B, Morrison BW, et al. Effects of
specific inhibition of cyclooxygenase-2 on sodium balance,
hemodynamics, and vasoactive eicosanoids. J Pharmacol Exp
Ther, 1999, 289:735–741.
Cheng K, Wu TJ, Wu KK, et al. Antagonism of the prostaglandin
D2 receptor 1 suppresses nicotinic acid-induced vasodilation
in mice and humans. Proc Natl Acad Sci U S A, 2006a,
103:6682–6687.
Cheng Y, Austin SC, Rocca B, et al. Role of prostacyclin in the
cardiovascular response to thromboxane A2. Science, 2002,
296:539–541.
Cheng Y, Wang M, Yu Y, et al. Cyclooxygenases, microsomal
prostaglandin E synthase-1, and cardiovascular function. J Clin
Invest, 2006b, 116:1391–1399.
Chiang N, Serhan CN, Dahlen SE, et al. The lipoxin receptor
ALX: Potent ligand-specific and stereoselective actions in
vivo. Pharmacol Rev, 2006, 58:463–487.
Coggins KG, Latour A, Nguyen MS, et al. Metabolism of PGE2
by prostaglandin dehydrogenase is essential for remodeling
the ductus arteriosus. Nat Med, 2002, 8:91–92.
Degousee N, Fazel S, Angoulvant D, et al. Microsomal
prostaglandin E2 synthase-1 deletion leads to adverse left ventricular
remodeling after myocardial infarction. Circulation,
2008, 117:1701–1710.
Dowd NP, Scully M, Adderley SR, et al. Inhibition of cyclooxygenase-2
aggravates doxorubicin-mediated cardiac injury in
vivo. J Clin Invest, 2001, 108:585–590.
Drazen JM. Asthma therapy with agents preventing leukotriene synthesis
or action. Proc Assoc Am Physicians, 1999, 111:547–559.
Evans JF, Ferguson AD, Mosley RT, Hutchinson JH. What’s all
the FLAP about?: 5-lipoxygenase-activating protein inhibitors
for inflammatory diseases. Trends Pharmacol Sci, 2008,
29:72–78.
Fabre JE, Nguyen M, Athirakul K, et al. Activation of the murine
EP3 receptor for PGE2 inhibits cAMP production and promotes
platelet aggregation. J Clin Invest, 2001, 107:603–610.
Fam SS, Morrow JD. The isoprostanes: Unique products of
arachidonic acid oxidation—A review. Curr Med Chem, 2003,
10:1723–1740.
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CHAPTER 33
LIPID-DERIVED AUTACOIDS: EICOSANOIDS AND PLATELET-ACTIVATING FACTOR