Page 329 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 17 Vasoactive Peptides 315

RAMP1 and thereby make them more selective for the CGRP ■ NEUROPEPTIDE Y
receptor. Examples are olcegepant and telcagepant.
Evidence is accumulating that release of CGRP from trigemi- The neuropeptide Y family is a multiligand/multireceptor system
nal nerves plays a central role in the pathophysiology of migraine. consisting of three polypeptide agonists that bind and activate
The peptide is released during migraine attacks, and successful four distinct receptors with different affinity and potency. The
treatment of migraine with a selective serotonin agonist normal- peptides are pancreatic polypeptide (PP), peptide YY (PYY),
izes cranial CGRP levels. Clinical trials showed olcegepant to be and neuropeptide Y (NPY). Each peptide consists of 36 amino
effective in treating migraine, but because of its low bioavailability, acids and has an amidated C-terminus. PP is secreted by the islets
it has to be administered by intravenous injection. Telcagepant is of Langerhans after food ingestion in proportion to the caloric
also effective and is orally active but has exhibited liver toxicity in content and appears to act mainly in the brainstem and vagus
a small number of patients. to promote appetite suppression, inhibit gastric emptying, and
increase energy expenditure; it also exerts direct actions in the
gut. PYY is released by entero-endocrine L cells of the distal gut
■ ADRENOMEDULLIN in proportion to food intake and produces anorexigenic effects.
NPY is one of the most abundant neuropeptides in both the
Adrenomedullin (AM) was first discovered in human adrenal central and peripheral nervous systems. Whereas PYY and PP act
medullary pheochromocytoma tissue. It is a 52-amino-acid as neuroendocrine hormones, NPY acts as a neurotransmitter.
peptide with a six-amino-acid ring and a C-terminal amidation In the sympathetic nervous system, NPY is frequently localized
sequence. Like CGRP, AM is a member of the calcitonin family in noradrenergic neurons and apparently functions both as a
of peptides. A related peptide termed adrenomedullin 2, also vasoconstrictor and as a cotransmitter with norepinephrine. The
called intermedin, has been identified in humans and other remainder of this section focuses on NPY.
mammals. NPY produces a variety of central nervous system effects,
AM is widely distributed in the body. The highest concentra- including increased feeding (it is one of the most potent orexigenic
tions are found in the adrenal glands, hypothalamus, and anterior molecules in the brain), hypotension, hypothermia, respiratory
pituitary, but high levels are also present in the kidneys, lungs, depression, and activation of the hypothalamic-pituitary-adrenal
cardiovascular system, and gastrointestinal tract. AM in plasma axis. Other effects include vasoconstriction of cerebral blood vessels,
apparently originates in the heart and vasculature. positive chronotropic and inotropic actions on the heart, and hyper-
In animals, AM dilates resistance vessels in the kidney, tension. The peptide is a potent renal vasoconstrictor and suppresses
brain, lung, hind limbs, and mesentery, resulting in a marked, renin secretion, but can cause diuresis and natriuresis. Prejunctional
long-lasting hypotension. The hypotension in turn causes neuronal actions include inhibition of transmitter release from sym-
reflex increases in heart rate and cardiac output. These pathetic and parasympathetic nerves. Vascular actions include direct
responses also occur during intravenous infusion of the peptide vasoconstriction, potentiation of the action of vasoconstrictors, and
in healthy human subjects. AM also acts on the kidneys to inhibition of the action of vasodilators. NPY promotes angiogenesis
increase sodium excretion and renin release, and it exerts other and cardiomyocyte remodeling.
endocrine effects including inhibition of aldosterone and insu- The diverse effects of NPY (and PP and PYY) are mediated by
lin secretion. It acts on the central nervous system to increase four subtypes of NPY receptors designated Y , Y , Y , and Y . All
2
1
5
4
2+
sympathetic outflow. are G protein-coupled receptors linked to mobilization of Ca
i
The diverse actions of AM are mediated by a receptor closely and inhibition of adenylyl cyclase. Y and Y receptors are of major
2
1
related to the CGRP receptor (see above). CLR co-assembles importance in the cardiovascular and other peripheral effects of the
with RAMP subtypes 2 and 3, thus forming the AM receptor. peptide. Y receptors have a high affinity for pancreatic polypeptide
4
Binding of AM to CLR activates G and triggers cAMP forma- and may be a receptor for the pancreatic peptide rather than for NPY.
s
tion in vascular smooth muscle cells, and increases nitric oxide Y receptors are found mainly in the central nervous system and may
5
production in endothelial cells. Other signaling pathways are be involved in the control of food intake. They also mediate the acti-
also involved. vation of the hypothalamic-pituitary-adrenal axis by NPY.
Circulating AM levels increase during intense exercise. Some selective nonpeptide NPY receptor antagonists are avail-
They also increase in a number of pathologic states, includ- able for research. The first nonpeptide Y receptor antagonist,
1
ing essential and pulmonary hypertension, acute myocardial BIBP3226, is also the most thoroughly studied. It has a short
infarction, and cardiac and renal failure. Plasma AM levels are half-life in vivo. In animal models, it blocks the vasoconstrictor
increased in proportion to the severity of these diseases and this and pressor responses to NPY. Structurally related Y antagonists
1
can be a useful prognostic marker. The roles of AM in these include BIB03304 and H409/22; the latter has been tested in
states remain to be defined, but it is currently thought that the humans. SR120107A and SR120819A are orally active Y antago-
1
peptide functions as a physiologic antagonist of the actions nists and have a long duration of action. BIIE0246 is the first
of vasoconstrictors including ET-1 and ANG II. By virtue of nonpeptide antagonist selective for the Y receptor; it does not
2
these actions, AM may protect against cardiovascular overload cross the blood-brain barrier. Useful Y antagonists are not avail-
4
and injury, and AM may be beneficial in the treatment of some able. The Y antagonists MK-0557 and S-2367 have been tested
5
cardiovascular diseases. in clinical trials for obesity.