Page 341 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 18 The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds 327

“relaxant” “contractile” “inhibitory” fMLP Receptor family

IP EP 2 EP 4 DP 1 TP FP EP 1 1 EP 3 DP 2/ 2
CR H
**
α s
β γ α 12/13
β γ α q β γ α i β γ

α 16 β γ +
RhoGEF
+
+
PLC-b
+
+
Rho activation Ca 2+
–
Biological Effects
Biologic Effects

cAMP

+ Adenylyl –
Cyclase
FIGURE 18–4 Prostanoid receptors and their signaling pathways. fMLP, formylated MetLeuPhe, a small peptide receptor; PLC-β,
phospholipase C-β. All of the receptors shown are of the seven-transmembrane, G protein-coupled type. The terms “relaxant,” “contractile,” and
**
“inhibitory” refer to the phylogenetic characterization of their primary effects. , all EP 3 isoforms couple through G i but some can also activate
G s or G 12/13 pathways. RhoGEF, rho guanine nucleotide exchange factor. See text for additional details.

Although prostanoids can activate peroxisome proliferator- is potentiated by exposure of smooth muscle cells to testosterone,
activated receptors (PPARs) if added in sufficient concentration which up-regulates smooth muscle cell TP expression. PGF
2α
in vitro, it remains questionable whether these compounds is also a vasoconstrictor but is not a smooth muscle mitogen.
ever attain concentrations sufficient to function as endogenous Another vasoconstrictor is the isoprostane 8-iso-PGF , also
2α
nuclear-receptor ligands in vivo. known as iPF III, which may act via the TP receptor.
2α
Vasodilator prostaglandins, especially PGI and PGE , pro-
2
2
Effects of Prostaglandins & Thromboxanes mote vasodilation by increasing cAMP and decreasing smooth
muscle intracellular calcium, primarily via the IP and EP recep-
4
The prostaglandins and thromboxanes have major effects on tors. Vascular PGI is synthesized by both smooth muscle and
2
smooth muscle in the vasculature, airways, and gastrointesti- endothelial cells, with the COX-2 isoform in the latter cell type
nal and reproductive tracts. Contraction of smooth muscle is being the major contributor. In the microcirculation, PGE is a
2
mediated by the release of calcium, while relaxing effects are vasodilator produced by endothelial cells. PGI inhibits prolifera-
2
mediated by the generation of cAMP. Many of the eicosanoids’ tion of smooth muscle cells, an action that may be particularly
contractile effects on smooth muscle can be inhibited by relevant in pulmonary hypertension. PGD may also function
2
lowering extracellular calcium or by using calcium channel- as a vasodilator, in particular as a dominant mediator of flushing
blocking drugs. Other important targets include platelets and induced by the lipid-lowering drug niacin.
monocytes, kidneys, the central nervous system, autonomic
presynaptic nerve terminals, sensory nerve endings, endocrine 2. Gastrointestinal tract—Most of the prostaglandins and
organs, adipose tissue, and the eye (the effects on the eye may thromboxanes activate gastrointestinal smooth muscle. Longi-
involve smooth muscle). tudinal muscle is contracted by PGE (via EP ) and PGF (via
2α
3
2
FP), whereas circular muscle is contracted strongly by PGF and
2α
A. Smooth Muscle weakly by PGI , and is relaxed by PGE (via EP ). Administration
4
2
2
1. Vascular—TXA is a potent vasoconstrictor. It is also a of either PGE or PGF results in colicky cramps (see Clinical
2α
2
2
smooth muscle cell mitogen and is the only eicosanoid that has Pharmacology of Eicosanoids, below). The leukotrienes also have
convincingly been shown to have this effect. The mitogenic effect powerful contractile effects.