Page 323 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 17 Vasoactive Peptides 309

share a common 17-amino-acid disulfide ring with variable C- and endothelium, kidneys, and intestine. It has not been found in sig-
N-terminals. A fourth peptide, urodilatin, has the same structure as nificant concentrations in the circulation. CNP has less natriuretic
ANP with an extension of four amino acids at the N-terminal. The and diuretic activity than ANP and BNP but is a potent vasodila-
renal effects of these peptides are discussed in Chapter 15. tor and may play a role in the regulation of peripheral resistance.
ANP is derived from the carboxyl terminal end of a common Urodilatin is synthesized in the distal tubules of the kidneys by
precursor termed preproANP. ANP is synthesized primarily in alternative processing of the ANP precursor. It elicits potent natri-
cardiac atrial cells, but it is also synthesized in ventricular myocar- uresis and diuresis, and thus functions as a paracrine regulator of
dium, by neurons in the central and peripheral nervous systems, sodium and water excretion. It also relaxes vascular smooth muscle.
and in the lungs.
The most important stimulus to the release of ANP from the
heart is atrial stretch via mechanosensitive ion channels. ANP Pharmacodynamics & Pharmacokinetics
release is also increased by volume expansion, changing from the The biologic actions of the natriuretic peptides are mediated
standing to the supine position, and exercise. ANP release can also through association with specific high-affinity receptors located
be increased by sympathetic stimulation via α adrenoceptors, on the surface of the target cells (Figure 17–5). Three recep-
1A
endothelins via the ET -receptor subtype (see below), glucocor- tor subtypes termed NPR-A (ANP-A), NPR-B (ANP-B), and
A
ticoids, and AVP. Plasma ANP concentration increases in several NPR-C (ANP-C) have been identified. The NPR-A and NPR-B
pathologic states, including heart failure, primary aldosteronism, receptors contain guanylyl cyclase at their intracellular domains.
chronic renal failure, and inappropriate ADH secretion syndrome. The primary ligands of the NPR-A receptor are ANP and BNP.
Administration of ANP increases sodium excretion and urine The NPR-B receptor is similar in structure to the ANP-A receptor,
flow. The ANP-induced natriuresis is due both to an increase but its primary ligand appears to be CNP. The NPR-C receptor
in glomerular filtration rate and a decrease in proximal tubular may be coupled to adenylyl cyclase or phospholipase C; it binds
sodium reabsorption. ANP also inhibits the release of renin, aldo- all three natriuretic peptides and functions as a clearance receptor.
sterone, and AVP; these changes may also increase sodium and The natriuretic peptides have a short half-life in the circula-
water excretion. Finally, ANP causes vasodilation and decreases tion. They are metabolized in the kidneys, liver, and lungs by
arterial blood pressure. Suppression of ANP production or block- the neutral endopeptidase NEP 24.11 (neprilysin). Inhibition of
ade of its action impairs the natriuretic response to volume expan- this endopeptidase results in increases in circulating levels of the
sion, and increases blood pressure. natriuretic peptides, natriuresis, and diuresis. The peptides are
Like ANP, BNP is synthesized primarily in the heart. Also like also removed from the circulation by binding to ANP-C receptors
ANP, the release of BNP appears to be volume related; indeed, in the vascular endothelium. This receptor binds the natriuretic
the two peptides may be co-secreted. BNP exhibits natriuretic, peptides with equal affinity. The receptor and bound peptide are
diuretic, and hypotensive activities similar to those of ANP but internalized, the peptide is degraded enzymatically, and the recep-
circulates at a lower concentration. tor is returned to the cell surface. Patients with heart failure have
CNP is located predominantly in the central nervous sys- high plasma levels of ANP and BNP; the latter has emerged as a
tem but is also present in other tissues including the vascular diagnostic and prognostic marker in this condition.

Extracellular
ANP=BNP CNP ANP=CNP>BNP
ANP=CNP>BNP
NPR-A GC-A NPR-A GC-A NPR-B GC-B NPR-B GC-B NPR-C NPR-C NEP Ring cleavage

Signaling?
Receptor Endocytosis ANP=CNP>BNP
recycling
Tail cleavage
GTP cGMP GTP cGMP
Peptide IDE
degradation

cGMP GTP cGMP GTP
Intracellular

FIGURE 17–5 Natriuretic hormone receptors, intracellular signaling, and degradation processes. GC-A, guanylate cyclase type A; GC-B,
guanylate cyclase type B; IDE, insulin degrading enzyme; NEP, neprilysin. (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.)