FIGURE 17–7 Comparison of the decrease in mortality produced by an angiotensin receptor blocker, a converting enzyme inhibitor, and the combined angiotensin-neprilysin inhibitor LCZ696 (Entresto) in patients with heart failure. Results for the three drugs are from separate trials. Each bar represents the drug effect versus placebo. (Adapted from Volpe M et al: The natriuretic peptides system in the pathophysiology of heart failure: From molecular basis to treatment. Clin Sci (Lond) 2016;130:57.) (FDA) for the treatment of heart failure with reduced ejection fraction (see Chapter 13). LCZ696 has also been shown to lower blood pressure in patients with essential hypertension, comparing favorably with valsartan. In a similar approach, a neprilysin inhibitor has been combined with an endothelin-converting enzyme inhibitor (see next section).
The endothelium is the source of a variety of substances with vasodilator (PGI2 and nitric oxide) and vasoconstrictor activities. The latter include the endothelin family, potent vasoconstrictor peptides that were first isolated from aortic endothelial cells.
Biosynthesis, Structure, & Clearance
Three isoforms of endothelin (ET) have been identified: the originally described ET, ET-1, and two similar peptides, ET-2 and ET-3. Each isoform is a product of a different gene and is synthesized as a prepro form that is processed to a propeptide and then to the mature peptide. Processing to the mature peptides occurs through the action of endothelin-converting enzyme. Each ET is a 21-amino-acid peptide containing two disulfide bridges.
ETs are widely distributed in the body. ET-1 is the predominant ET secreted by the vascular endothelium. It is also produced by neurons and astrocytes in the central nervous system and in endometrial, renal mesangial, Sertoli, breast epithelial, and other cells. ET-2 is produced predominantly in the kidneys and intestine, whereas ET-3 is found in highest concentration in the brain but is also present in the gastrointestinal tract, lungs, and kidneys. ETs are present in the blood in low concentration; they apparently 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 and cytokines, including TGF-β and interleukin 1 (IL-1), vasoactive substances including ANG II and AVP, and mechanical stress. Expression is inhibited by nitric oxide, prostacyclin, and ANP.
Clearance of ETs from the circulation is rapid and involves both enzymatic degradation by NEP 24.11 (neprilysin) and clearance by the ETB receptor.
Two ET receptor subtypes, termed ETA and ETB, are widely distributed in the body. ETA receptors have a high affinity for ET-1 and a low affinity for ET-3 and are located on smooth muscle cells, where they mediate vasoconstriction (Figure 17–8). ETB receptors have approximately equal affinities for ET-1 and ET-3 and are primarily located on vascular endothelial cells, where they mediate release of PGI2 and nitric oxide. Some ETB receptors are also present on smooth muscle cells and mediate vasoconstriction. Both receptor subtypes belong to the G protein-coupled seventransmembrane domain family of receptors.