Page 340 - Basic _ Clinical Pharmacology ( PDFDrive )

326 SECTION IV Drugs with Important Actions on Smooth Muscle

+
K channels. This results in smooth muscle cell hyperpolarization and on the cell surface, with pharmacologic specificity determined by
vasodilation, leading to reduced blood pressure. Substantial evidence receptor density and type on different cells (Figure 18–4). A single
indicates that EETs may function as endothelium-derived hyper- gene product has been identified for each of the PGI (IP), PGF
2
2α
polarizing factors, particularly in the coronary circulation. 15(S)- (FP), and TXA (TP) receptors, while four distinct PGE receptors
2
2
Hydroxy-11,12-EET, which arises from the 15-LOX pathway, is also (EPs 1–4) and two PGD receptors (DP and DP ) have been cloned.
2
2
1
an endothelium-derived hyperpolarizing factor and a substrate for Additional isoforms of the human TP (α and β), FP (A and B), and
sEH. Consequently, there is interest in inhibitors of soluble sEH as EP (Ia, Ib, Ic, II, III, IV, and e) receptors can arise through differen-
3
potential antithrombotic and antihypertensive drugs. An exception to tial mRNA splicing. Two receptors exist for LTB (BLT and BLT )
2
1
4
the general response to EETs as vasodilators is the pulmonary vascu- and for LTC /LTD (cysLT and cysLT ). It appears that LTE func-
4
4
2
4
1
lature where they cause vasoconstriction. It is unclear yet whether this tions through one or more receptors distinct from cysLT /cysLT ,
1
2
activity of EETs may limit the potential clinical use of sEH inhibitors. with some evidence that the orphan receptor GPR99 and the ADP
Down-regulation of pulmonary sEH may contribute to pulmonary receptor P2Y may function as LTE receptors. The formyl peptide
12
4
hypertension. Anti-inflammatory, antiapoptotic, and proangiogenic (fMLP)-1 receptor can be activated by lipoxin A4 and consequently
actions of the EETs have also been reported. has been termed the ALX receptor. Receptor heterodimerization has
been reported for a number of the eicosanoid receptors, providing
Isoeicosanoids for additional receptor subtypes from the currently identified gene
The isoeicosanoids, a family of eicosanoid isomers, are formed non- products. All of these receptors are G protein-coupled; properties of
enzymatically by direct free radical-based action on AA and related the best-studied receptors are listed in Table 18–1.
lipid substrates. The isoprostanes thus formed are prostaglandin EP , EP , IP, and DP receptors activate adenylyl cyclase via G .
4
1
s
2
stereoisomers. Because prostaglandins have many asymmetric This leads to increased intracellular cAMP levels, which in turn
centers, they have a large number of potential stereoisomers. COX activate specific protein kinases (see Chapter 2). EP , FP, and TP
1
is not needed for the formation of the isoprostanes, and its inhibi- activate phosphatidylinositol metabolism, leading to the forma-
tion with aspirin or other NSAIDs should not affect the isoprostane tion of inositol trisphosphate, with subsequent mobilization of
2+
2+
pathway. The primary epimerization mechanism is peroxidation Ca stores and an increase of free intracellular Ca . TP also cou-
of arachidonate by free radicals. Peroxidation occurs while arachi- ples to multiple G proteins, including G 12/13 and G , to stimulate
16
donic acid is still esterified to the membrane phospholipids. Thus, small G protein signaling pathways, and may activate or inhibit
unlike prostaglandins, these stereoisomers are “stored” as part of adenylyl cyclase via G (TPα) or G (TPβ), respectively. EP iso-
i
3
s
the membrane. They are then cleaved by phospholipases, circulate, forms can couple to both increased intracellular calcium and to
and are excreted in urine. Isoprostanes are present in relatively large increased or decreased cAMP. The DP receptor (also known as
2
amounts (tenfold greater in blood and urine than the COX-derived the chemoattractant receptor-homologous molecule expressed on
prostaglandins). They have potent vasoconstrictor effects when Th2 cells, or CRTh2), which is unrelated to the other prostanoid
infused into renal and other vascular beds and may activate pros- receptors, is a member of the fMLP receptor superfamily. This
tanoid receptors. They also may modulate other aspects of vascular receptor couples through a G -type G protein and leads to inhibi-
i
2+
function, including leukocyte and platelet adhesive interactions and tion of cAMP synthesis and increases in intracellular Ca in a
angiogenesis. It has been speculated that they may contribute to the variety of cell types.
pathophysiology of inflammatory responses in a manner insensitive LTB also causes inositol trisphosphate release via the BLT
4
1
to COX inhibitors. A particular difficulty in assessing the likely receptor, causing activation, degranulation, and superoxide anion
biologic functions of isoprostanes—several of which have been generation in leukocytes. The BLT receptor, a low-affinity recep-
2
shown to serve as incidental ligands at prostaglandin receptors—is tor for LTB , is also bound with reasonable affinity by 12(S)- and
4
that while high concentrations of individual isoprostanes may be 12(R)-HETE, although the biologic relevance of this observation
necessary to elicit a response, multiple compounds are formed is not clear. CysLT and cysLT couple to G , leading to increased
q
1
2
2+
coincidentally in vivo under conditions of oxidant stress. Analogous intracellular Ca . Studies have also placed G i downstream of
leukotriene and EET isomers have been described. cysLT 2 . An orphan receptor, GPR17, binds cysLTs and may
negatively regulate the function of cysLT , but its physiologic
1
■ BASIC PHARMACOLOGY OF role remains ill defined. As noted above, the EETs promote vaso-
dilation via paracrine activation of calcium-activated potassium
EICOSANOIDS channels on smooth muscle cells leading to hyperpolarization and
relaxation. This occurs in a manner consistent with activation of
MECHANISMS & EFFECTS OF a G -coupled receptor, although a specific EET receptor has yet to
s
EICOSANOIDS be identified. EETs may also act in an autocrine manner directly
activating endothelial transient receptor potential channels to
cause endothelial hyperpolarization, which is then transferred
Receptor Mechanisms to the smooth muscle cells by gap junctions or potassium ions.
As a result of their short half-lives, the eicosanoids act mainly in an Specific receptors for isoprostanes have not been identified, and
autocrine and a paracrine fashion, ie, close to the site of their synthe- the biologic importance of their capacity to act as incidental
sis, and not as circulating hormones. These ligands bind to receptors ligands at prostaglandin receptors remains to be established.