Page 325 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 17 Vasoactive Peptides 311

(FDA) for the treatment of heart failure with reduced ejection endometrial, renal mesangial, Sertoli, breast epithelial, and other
fraction (see Chapter 13). LCZ696 has also been shown to lower cells. ET-2 is produced predominantly in the kidneys and intes-
blood pressure in patients with essential hypertension, compar- tine, whereas ET-3 is found in highest concentration in the brain
ing favorably with valsartan. In a similar approach, a neprilysin but is also present in the gastrointestinal tract, lungs, and kidneys.
inhibitor has been combined with an endothelin-converting ETs are present in the blood in low concentration; they apparently
enzyme inhibitor (see next section). mainly act locally in a paracrine or autocrine fashion rather than
as circulating hormones.
The expression of the ET-1 gene is increased by growth factors
■ ENDOTHELINS and cytokines, including TGF-β and interleukin 1 (IL-1), vasoac-
tive substances including ANG II and AVP, and mechanical stress.
The endothelium is the source of a variety of substances with Expression is inhibited by nitric oxide, prostacyclin, and ANP.
vasodilator (PGI and nitric oxide) and vasoconstrictor activities. Clearance of ETs from the circulation is rapid and involves
2
The latter include the endothelin family, potent vasoconstrictor both enzymatic degradation by NEP 24.11 (neprilysin) and clear-
peptides that were first isolated from aortic endothelial cells. ance by the ET receptor.
B
Biosynthesis, Structure, & Clearance Actions

Three isoforms of endothelin (ET) have been identified: the Two ET receptor subtypes, termed ET and ET , are widely dis-
B
A
originally described ET, ET-1, and two similar peptides, ET-2 and tributed in the body. ET receptors have a high affinity for ET-1
A
ET-3. Each isoform is a product of a different gene and is synthe- and a low affinity for ET-3 and are located on smooth muscle
sized as a prepro form that is processed to a propeptide and then cells, where they mediate vasoconstriction (Figure 17–8). ET
B
to the mature peptide. Processing to the mature peptides occurs receptors have approximately equal affinities for ET-1 and ET-3
through the action of endothelin-converting enzyme. Each ET is and are primarily located on vascular endothelial cells, where they
a 21-amino-acid peptide containing two disulfide bridges. mediate release of PGI and nitric oxide. Some ET receptors are
B
2
ETs are widely distributed in the body. ET-1 is the predomi- also present on smooth muscle cells and mediate vasoconstriction.
nant ET secreted by the vascular endothelium. It is also produced Both receptor subtypes belong to the G protein-coupled seven-
by neurons and astrocytes in the central nervous system and in transmembrane domain family of receptors.

Low shear High shear
stress stress
Blood ANG II NO
Cytokines PGI 2
Thrombin ANP
+ –
ET
B
Vascular PreproET-1 BigET-1 ECE ET-1
endothelium L-Arg NO
PGI 2

ET-1 NO PGI 2
Interstitium

ET ET B
A
Vasoconstriction Vasodilation
Proliferation Antiproliferation
Vascular
smooth muscle

FIGURE 17–8 Generation of endothelin-1 (ET-1) in the vascular endothelium, and its direct and indirect effects on smooth muscle cells
mediated by ET A and ET B receptors. ANG II, angiotensin II; ANP, atrial natriuretic peptide; Arg, arginine; BigET-1, proET-1; ECE, endothelial-
converting enzyme; NO, nitric oxide; PreproET-1, precursor of BigET-1; PGI 2 , prostaglandin I 2 .