Page 343 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 18 The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds 329

3. Airways—Respiratory smooth muscle is relaxed by PGE and receptors), whereas higher concentrations inhibit (via IP recep-
2
PGI and contracted by PGD , TXA , and PGF . Studies of DP tors), platelet aggregation. PGD 2 inhibits aggregation via DP ,
1
2α
2
2
1
2
and DP receptor knockout mice suggest an important role of this leading to increased cAMP generation.
2
prostanoid in asthma, although the DP receptor appears more
2
relevant to allergic airway diseases. The cysteinyl leukotrienes are C. Kidney
also bronchoconstrictors. They act principally on smooth muscle Both the medulla and the cortex of the kidney synthesize prosta-
in peripheral airways and are a thousand times more potent than glandins, the medulla substantially more than the cortex. COX-1
histamine, both in vitro and in vivo. They also stimulate bron- is expressed mainly in cortical and medullary collecting ducts
chial mucus secretion and cause mucosal edema. Bronchospasm and mesangial cells, arteriolar endothelium, and epithelial cells
occurs in about 10% of people taking NSAIDs, possibly because of Bowman’s capsule. COX-2 is restricted to the renal medullary
of a shift in arachidonate metabolism from COX metabolism to interstitial cells, the macula densa, and the cortical thick ascend-
leukotriene formation. ing limb.
The major renal eicosanoid products are PGE and PGI ,
2
2
4. Reproductive—The actions of prostaglandins on reproduc- followed by PGF and TXA . The kidney also synthesizes several
2α
2
tive smooth muscle are discussed below under section D, Repro- hydroxyeicosatetraenoic acids, leukotrienes, cytochrome P450 prod-
ductive Organs. ucts, and epoxides. Prostaglandins play important roles in maintain-
ing blood pressure and regulating renal function, particularly in
B. Platelets marginally functioning kidneys and volume-contracted states.
Platelet aggregation is markedly affected by eicosanoids. PGI , a Under these circumstances, renal cortical COX-2-derived PGE
2
2
major product of endothelial-derived COX-2, is a potent inhibitor and PGI maintain renal blood flow and glomerular filtration rate
2
of platelet aggregation. This inhibition occurs via an IP receptor- through their local vasodilating effects. These prostaglandins also
dependent elevation in G activity and cAMP. Dysfunctional modulate systemic blood pressure through regulation of water and
s
genetic variants in the human prostacyclin receptor as well as sodium excretion. Expression of medullary COX-2 and mPGES-1
drug inhibition of COX-2 (reducing prostacyclin signaling and is increased under conditions of high salt intake. COX-2-derived
production, respectively) lead to increased platelet activation and prostanoids increase medullary blood flow and inhibit tubular
aggregation. This has recently been demonstrated to have major sodium reabsorption, while COX-1-derived products promote salt
implications regarding adverse cardiovascular events, as described excretion in the collecting ducts. Increased water clearance probably
below (see Inhibition of Eicosanoid Synthesis). TXA is the major results from an attenuation of the action of antidiuretic hormone
2
product of platelet COX-1, the only COX isoform expressed (ADH) on adenylyl cyclase. Loss of these effects may underlie the
in mature platelets, with COX-1-derived PGD found in lesser systemic or salt-sensitive hypertension often associated with COX
2
amounts. TXA is a powerful inducer of platelet aggregation. inhibition. A common misperception—often articulated in discus-
2
TXA additionally amplifies the effects of other, more potent, sion of the cardiovascular toxicity of drugs such as rofecoxib—is
2
platelet agonists such as thrombin. The TP-G signaling pathway that hypertension secondary to NSAID administration is somehow
q
2+
elevates intracellular Ca and activates protein kinase C, facilitat- independent of the inhibition of prostaglandins. Loop diuretics,
ing platelet aggregation and TXA biosynthesis. Activation of G / eg, furosemide, produce some of their effect by stimulating COX
12
2
G induces Rho/Rho-kinase–dependent regulation of myosin activity. In the normal kidney, this increases the synthesis of the
13
light chain phosphorylation leading to platelet shape change. vasodilator prostaglandins. Therefore, patient response to a loop
Mutations in the human TP have been associated with mild diuretic is diminished if a COX inhibitor is administered concur-
bleeding disorders. The platelet actions of TXA are restrained in rently (see Chapter 15).
2
vivo by PGI , which inhibits platelet aggregation by all recognized There is an additional layer of complexity associated with
2
agonists, and PGD . Platelet COX-1-derived TXA biosynthesis the effects of renal prostaglandins. In contrast to the medullary
2
2
is increased during platelet activation and aggregation and is enzyme, cortical COX-2 expression is increased by low salt intake,
irreversibly inhibited by chronic administration of aspirin at low leading to increased renin release. This elevates glomerular filtra-
doses. Urinary metabolites of TXA increase in clinical syndromes tion rate and contributes to enhanced sodium reabsorption and a
2
of platelet activation, such as diabetes mellitus, and particularly rise in blood pressure. PGE 2 is thought to stimulate renin release
in patients with myocardial infarction and stroke. Macrophage through activation of EP or EP . PGI can also stimulate renin
4
2
2
COX-2 appears to contribute roughly 10% of the increment in release and this may be relevant to maintenance of blood pressure
TXA biosynthesis observed in smokers, while the rest is derived in volume-contracted conditions and to the pathogenesis of reno-
2
from platelet COX-1. A variable contribution, presumably from vascular hypertension. Inhibition of COX-2 may reduce blood
macrophage COX-2, may be insensitive to the effects of low-dose pressure in these settings.
aspirin. In a single trial comparing low- and high-dose aspirin, TXA causes intrarenal vasoconstriction (and perhaps an
2
no increase in benefit was associated with increased dose; in ADH-like effect), resulting in a decline in renal function. The
fact, this study, as well as indirect comparisons across placebo- normal kidney synthesizes only small amounts of TXA . However,
2
controlled trials, suggests an inverse dose-response relationship, in renal conditions involving inflammatory cell infiltration (such
perhaps reflecting increasing inhibition of PGI synthesis at higher as glomerulonephritis and renal transplant rejection), the inflam-
2
doses of aspirin. Low concentrations of PGE enhance (via EP matory cells (monocyte-macrophages) release substantial amounts
3
2