CHAPTER X: ADRENOCEPTOR ANTAGONIST DRUGS

VI Endothelins
A Biosynthesis, Structure, & Clearance
OUTLINE B Action
I Introduction C Inhibitors of Endothelin Synthesis & Action
II Angiotensin i Physiologic & Pathologic Roles of
A Biosynthesis of Angiotensin Endothelin
i Renin VII Vasoactive Intestinal Peptide
ii Control of Renin Release VIII Substance P
iii Angiotensinogen IX Neurotensin
iv Angiotensin I X Calcitonin Gene-Related Peptide
v Converting Enzyme XI Adrenomedullin
vi Angiotensinasel XII Neuropeptide Y
B Action of Angiotensin II XIII Urotensin
i Blood Pressure
ii Adrenal Cortex and Kidney
iii Central Nervous System
iv Cell Growth INTRODUCTION
C Angiotensin Receptors & Mechanism of
Action Peptides
i Angiotensin Receptors ● are used by most tissues for cell-to-cell
ii Prorenin Receptors communication.
D Inhibition of the Renin-Angiotensin System ● They play important roles as transmitters in the
i Drugs that Block Renin Release autonomic and central nervous systems.
ii Renin Inhibitors Investigation showed that they play important
iii Angiotensin-Converting Enzyme roles not only in physiologic regulation but also
Inhibitors in a variety of disease states.
iv Angiotensin Receptor Blockers ● exert important direct effects on vascular and
v Angiotensin Receptor Blockers other smooth muscles.
vi Summary: Renin-Angiotensin System ○ These peptides include:
III Kinins ■ vasoconstrictors (angiotensin
A Biosynthesis of Kinins II, vasopressin, endothelins,
i Kallikreins neuropeptide Y, and urotensin)
ii Kininogens
B Formation ■ vasodilators (bradykinin and
C Physiologic & Pathologicl Effects of Kinins related kinins, natriuretic
i Effects on the Cardiovascular System peptides, vasoactive intestinal
ii Effect on Endocrine & Exocrine Glands peptide, substance P,
iii Role in Inflammation &Pain neurotensin, calcitonin
iv Role in Hereditary Angioedema gene-related peptide, and
v Other Effects adrenomedullin).
D Kinin Receptors & Mechanism of Action
E Drug Affecting the Kallikrein-Kenin System ANGIOTENSIN
IV Vasopressin BIOSYNTHESIS OF ANGIOTENSIN
A Vasopressin Receptors, Agonists, and
Antagonists The principal steps include:
V Natriuretic Peptides ● enzymatic cleavage of angiotensin I (ANG I)
A Synthesis of Structure from angiotensinogen by renin;
B Pharmacodynamics & Pharmacokinetics
C Clinical Role of Natriuretic Peptides

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 CHAPTER VI:INTRODUCTION TO AUTONOMIC PHARMACOLOGY
● conversion of ANG I to ANG II by converting
enzyme, and degradation of ANG II by several
peptidases.
RENIN
Renin
- is an aspartyl protease enzyme
- catalyzes the hydrolytic release of the
decapeptide ANG I from angiotensinogen.
- synthesized as a prepromolecule that is first
processed to prorenin and then to active renin
by cleavage of a 43-amino acid N-terminal
prosegment.
XActive renin
- is a glycoprotein consisting of 340 amino acids.
- In the circulation - originates in the kidneys and
disappears entirely after nephrectomy.
- Within the kidney, renin is synthesized and
stored in the juxtaglomerular apparatus of the
nephron.
Juxtaglomerular cells
- specialized granular cells
- are the site of synthesis, storage, and release of
renin.
Macula Densa
- is a specialized segment of the nephron that is
closely associated with the vascular components
of the juxtaglomerular apparatus.
Sympathetic nervous system
- innervates the vascular and tubular components
of the juxtaglomerular apparatus, including the
juxtaglomerular cells.
Prorenin
- is present in the circulation at levels higher than
those of active renin.
- Plasma prorenin levels decrease after
nephrectomy, but significant amounts remain.
The remaining prorenin is thought to originate in
extrarenal tissues including the adrenal gland,
ovaries, testes, placenta, and retina.
- Plasma prorenin may exert actions via a unique
prorenin receptor.
CONTROL OF RENIN RELEASE
The rate at which renin is released by the kidneys is
the primary determinant of the activity of the
renin-angiotensin system.
Blood Pressure and Renin Release is inversely
proportional
Active renin is released by exocytosis immediately
upon stimulation of the juxtaglomerular apparatus.
Prorenin is released constitutively, usually at a rate
higher than that of active renin, thus accounting for the
fact that prorenin can constitute 80–90% of the total
renin in the circulation.
Active renin release is controlled by a variety of
factors, including the macula densa, a renal vascular
receptor, the sympathetic nervous system, and ANG II.
For an easier understanding of the factors. Please refer
to this video:
https://www.youtube.com/watch?v=DPpOR3-s17w&ab_c
hannel=ArmandoHasudungan
Macula Densa
- a structure that has a close anatomic
association with the afferent arteriole.
● The initial step involves the detection of some
function of NaCl concentration in, or delivery
to, the distal tubule, possibly by the Na+ /K+
/2Cl− cotransporter.
● The macula densa then signals changes in
renin release by the juxtaglomerular cells
such that there is an inverse relationship
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 CHAPTER VI:INTRODUCTION TO AUTONOMIC PHARMACOLOGY
between NaCl delivery or concentration and
renin release.
○ When NaCl decrease, the macula densa
stimulates the juxtaglomerular cells to
produce or release renin. SAME
happens when there are too much
(increases level) NaCl, they send
signals to the juxtaglomerular cells to
stop producing renin. [renin is important
in the reabsorption of sodium for the
regulation of blood pressure and fluid
balance]
Potential candidates for signal transmission:
● prostaglandin E2 (PGE2) and nitric oxide
which stimulate renin release.
● adenosine, which inhibits the stimulus of renin
release.
○ Because the sodium intake in the
general population is high, macula
densa-mediated renin secretion is
usually at basal levels, increasing only
when sodium intake decreases.
Renal Baroceptor
renal vascular baroreceptor mediates an inverse
relationship between renal artery pressure and renin
release.
Juxtaglomerular cells are sensitive to stretch and that
increased stretch results in decreased renin release.
- The decrease may result from influx of calcium
which, inhibits renin release. The paracrine
factors PGE2, nitric oxide, and adenosine have
also been implicated in the baroreceptor control
of renin release.
At normal blood pressure, renal baroreceptor-mediated
renin secretion is low; it increases in hypotensive
states.
Kay ani man gud ni guysu. At normal blood pressure
kuno, our juxtaglomerular cells are only producing a few
renin (which is why low nang naa sa taas). Your
baroreceptors, which are a group of receptors that
detects changes in blood pressure, will inform your
juxtaglomerular cells to produce more to increase the
pressure.
Sympathetic Nervous System
Norepinephrine
- released from renal sympathetic nerves
stimulates renin release
- Indirectly by α-adrenergic activation of
the renal baroreceptor and macula
densa mechanisms.
- Directly by an action on the
juxtaglomerular cells.
- direct effect is mediated by β1
adrenoceptors.
- Through this mechanism, reflex
activation of the sympathetic
nervous system by hypotension
or hypovolemia leads to
activation of the
renin-angiotensin system.
This is very important during sympathetic activity or “fight
or flight” response, especially during HYPOtension since
this is what stimulates the juxtaglomerular cells (by β1
adrenoceptors) to release renin into the bloodstream and
be converted into ANG II (activation of renin-angiotensin
system), which will constrict the blood vessel for blood
pressure increase.
Angiotensin
ANG II
- inhibits renin release. (results from increased
blood pressure acting by way of the renal
baroreceptor and macula densa mechanisms,
and from a direct action of the peptide on the
juxtaglomerular cells.)
- The direct inhibition is mediated by
increased intracellular Ca2+
concentration and forms the basis of a
short-loop negative feedback
mechanism controlling renin release.
Interruption of this feedback with drugs
that inhibit the renin-angiotensin system
results in stimulation of renin release.
ANG II role is to constrict the blood vessel to increase
the blood pressure. The increase of your blood pressure
is a negative feedback of ANG II to your juxta or this
serves as a signal to your juxtaglomerular cells to stop
producing more renin. So in the case of hypotensivity, eh
inhibit ang ANG II kay para magrelease balik imo juxta
cells og renin.
Intracellular Signaling Pathways
The release of renin by the juxtaglomerular cells is
controlled by the interplay among three intracellular
messengers:
● cAMP,
● cyclic guanosine monophosphate (cGMP),
● free cytosolic Ca2+ concentration.
cAMP
● plays a major role; maneuvers that increase
cAMP levels, including
○ activation of adenylyl cyclase
○ inhibition of cAMP phosphodiesterases
○ administration of cAMP analogs,
increase renin release.
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 CHAPTER VI:INTRODUCTION TO AUTONOMIC PHARMACOLOGY
Increases in intracellular Ca2+ can result from
increased entry of extracellular Ca2+ or mobilization of
Ca2+ from intracellular stores, while;
Increases in cGMP levels can result from activation of
soluble or particulate guanylyl cyclase.
Ca2+ and cGMP appear to alter renin release indirectly,
primarily by changing cAMP levels.
Pharmacologic Alteration of Renin Release
The release of renin is altered by a wide variety of
pharmacologic agents. It is stimulated by:
● vasodilators (hydralazine, minoxidil,
nitroprusside),
● β-adrenoceptor agonists,
● α-adrenoceptor antagonists,
● phosphodiesterase inhibitors (eg,
theophylline, milrinone, rolipram)
● most diuretics and anesthetics.
This stimulation can be accounted for by the control
mechanisms just described.
ANGIOTENSINOGEN
Angiotensinogen
- is the circulating protein substrate from which
renin cleaves ANG I. It is inactive.
- It is synthesized in the liver.
- the concentration of angiotensinogen in the
circulation is less than the Km of the
renin-angiotensinogen reaction and is,
therefore, a determinant of the rate of formation
of angiotensin.
- It is elevated during pregnancy and in women
taking estrogen-containing oral contraceptives.
The production of angiotensinogen is increased by:
● corticosteroids
● estrogen
● thyroid hormones
● ANG II.
The increased plasma angiotensinogen concentration is
thought to contribute to hypertension that may occur in
these situations.
ANGIOTENSIN I
● Although it contains the peptide sequences
necessary for all of the actions of the
renin-angiotensin system, it has little or no
biologic activity. Instead, it must be converted to
ANG II by converting enzyme.
● may also be acted on by plasma or tissue
aminopeptidases to form [des-Asp1 ]angiotensin
I; this in turn is converted to [des-Asp1
]angiotensin II (commonly known as angiotensin
III) by converting enzyme.
CONVERTING
ENZYME(ANGIOTENSIN-CONVERTING ENZYME
[ACE], PEPTIDYL DIPEPTIDASE, KININASE II)
Converting enzyme
● is a dipeptidyl carboxypeptidase with two active
sites that catalyzes the cleavage of dipeptides
from the carboxyl-terminal of certain peptides.
● Its most important substrates are
○ ANG I, which it converts to ANG II,
○ bradykinin, which it inactivates.
● It also cleaves enkephalins and substance P
(but the physiologic significance of these effects
has not been established.)
● Its action is prevented by a penultimate prolyl
residue in the substrate, and ANG II is therefore
not hydrolyzed by converting enzyme.
ACE2
● is highly expressed in vascular endothelial cells
of the kidneys, heart, and testes.
● has only one active site and functions as a
carboxypeptidase rather than a dipeptidyl
carboxypeptidase.
● differs from ACE in that it does not hydrolyze
bradykinin and is not inhibited by converting
enzyme inhibitors
● It removes a single amino acid from the
C-terminal of ANG I forming ANG 1-9, which is
inactive but is converted to ANG 1-7 by ACE.
ACE2 also converts ANG II to ANG 1-7.
○ ANG 1-7 has vasodilator activity,
apparently mediated by the orphan
heterotrimeric guanine
nucleotide-binding protein-coupled
receptor (Mas receptor).
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 CHAPTER VI:INTRODUCTION TO AUTONOMIC PHARMACOLOGY
○ This vasodilation may serve to
○ BRAIN -because the
counteract the vasoconstrictor activity of
peptide
ANG II.
simultaneously acts
on the brain to reset
(FIGURE 17-3)
the baroreceptor
reflex control of
heart rate to a higher
pressure.
○ AUTONOMIC
NERVOUS SYSTEM
- ANG II interacts to
stimulate autonomic
ganglia, increase the
release of
epinephrine, and
norepinephrine.

Adrenal ● Zona Glomerulosa in the

Cortex & Adrenal Cortex
Kidney ○ Synthesis and
release of
aldosterone (ANG II
direct action to zona
glomerulosa of the
adrenal cortex.)
● Kidney
○ Renal
ANGIOTENSINASE vasoconstriction,
○ increase proximal
- A variety of peptidase that removes ANG II (has tubular sodium
a plasma half-life of 15-16 seconds) from the reabsoption,
circulation. ○ Inhibit release of
renin.
ANG II is metabolized during passage through most
vascular beds (a notable exception being the lung). Central ● stimulate drinking
Most metabolites of ANG II are biologically inactive, but nervous (dipsogenic effect)
the initial product of aminopeptidase action—[des-Asp1 system ● increase the secretion of
]angiotensin II or angiotensin III—retains some biologic vasopressin
activity. ● Increase secretion of
adrenocorticotropic hormone
ACTION OF ANGIOTENSIN II (ACTH)

ANG II exerts important actions at vascular smooth Although the physiological

muscle, adrenal cortex, kidney, heart, and brain via the significance of these effects is not
receptors described below. Through these actions, the known.
renin-angiotensin system plays a key role in the
regulation of fluid and electrolyte balance and arterial Cell Growth ● Promotes miitogenicity
blood pressure. Excessive activity of the (produce, or stimulate
renin-angiotensin system can result in hypertension and mitosis) on vascular and
disorders of fluid and electrolyte homeostasis. cardiac muscle cells.

The stimulation of vascular and

Blood ● ANG II pressor response is
cardiac growth by ANG II is mediated
Pressure due to direct contraction of
by other pathways, probably receptor
vascular— especially
and nonreceptor tyrosine kinases
arteriolar-smooth muscle.
such as the Janus tyrosine kinase
● increase blood pressure
Jak2, and by increased transcription
through actions in the:
of specific genes.

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 CHAPTER VI:INTRODUCTION TO AUTONOMIC PHARMACOLOGY

ANGIOTENSIN RECEPTORS & MECHANISM OF PRORENIN RECEPTORS

ACTION
ANGIOTENSIN RECEPTORS Prorenin is an inactive precursor of renin, with no
receptor or function of its own, despite its high levels in
ANG II receptors the circulation.
- are widely distributed in the body.
- are G protein-coupled and located on the Novel Receptor ((Pro) renin receptor)
plasma membrane of target cells. - This receptor binds both renin and prorenin and
- permits rapid onset of the various actions of is therefore referred to as the (pro)renin
ANG II. receptor.
- It is a ubiquitously expressed 350-amino acid
Two distinct subtypes of ANG II receptors: ANG II protein with a single transmembrane domain
binds equally to both subtypes that binds prorenin to a large N-terminal
extracellular domain.
AT1 AT2
When prorenin binds to the (pro)renin receptor, the
prorenin undergoes a conformational change and
● Vasoconstriction ● Vasodilation
becomes enzymatically active without cleavage of the
(serves to
prosegment. This is referred to as nonproteolytic to
● Predominates in counteract
distinguish it from the proteolytic activation with
the vascular vasoconstriction
prosegment removal that occurs in the kidney.
smooth muscles mediated by AT1)
(based on figure 17-3) To make it simple: Prorenin and
● A Gq ● present at high
renin bind together to the (pro)renin receptors producing
protein-coupled density in all
a non-proteolytic activation in tissues stimulating
receptor. tissues during
inflammation, proliferation and hypertrophy.
fetal development
(nonproteolytic - meaning no proteins are broken down
● Binding of ANG II and may play an
into peptides or amino acids)
to AT1 receptors in important role in
vascular smooth regulating cellular
Binding of prorenin to the receptor activates
muscle results in differentiation and
intracellular signaling pathways that differ depending
activation of organ
on the cell type.
phospholipase C development by
- For example, in mesangial and vascular
and generation of virtue .
smooth muscle cells, prorenin binding
inositol
activates MAP kinases and expression of
trisphosphate ● nitric
profibrotic molecules. Thus, elevated prorenin
and oxide-dependent
levels (as occur, for example, in diabetes
diacylglycerol. and may involve
mellitus) might have adverse effects via
the bradykinin B2
angiotensin-dependent and -independent
receptor-nitric
pathways (Figure 17–3).
oxide-cGMP
pathway
Handle region peptide (HRP)
● consists of the amino acid sequence
corresponding to the “handle” region of the
prorenin prosegment.
● synthesized and shown to competitively inhibit
binding of prorenin to the (pro)renin receptor.
AT2 expression declines rapidly to an undetectable ● has been reported to have beneficial effects in
level in many tissues after birth, but low levels remain in the kidneys of diabetic rats.
the heart, adrenal gland, kidney, brain, and reproductive ○ PRO20
tissues. ■ A newer putative (pro)renin
receptor antagonist
In animal studies, activation of AT2 receptors has been ■ has been reported to lower
reported to produce anti-inflammatory, antiproliferative, blood pressure in an animal
antihypertrophic, antifibrotic, proapoptotic, and model of hypertension.
vasodilatory effects
Note that the concentration of prorenin required to
activate (pro)renin receptors is very high, much higher
than that occurring under physiologic conditions.

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 CHAPTER VI:INTRODUCTION TO AUTONOMIC PHARMACOLOGY
INHIBITION OF THE RENIN-ANGIOTENSIN
SYSTEM
DRUGS THAT BLOCK RENIN RELEASE
Drugs that block the sympathetic nervous system inhibit
the release of renin.
● Propranolol
● β-adrenoceptor blocking drugs, which act by
blocking the renal β receptors involved in the
sympathetic control of renin release.
RENIN INHIBITORS
Cleavage of angiotensinogen by renin is the
rate-limiting step in the formation of ANG II and thus
represents a logical target for inhibition of the
renin-angiotensin system.
Aliskiren
- was the first nonpeptide renin inhibitor to be
approved for the treatment of hypertension.
- decreases baseline plasma renin activity in
hypertensive subjects.
- eliminates the rise produced by ACE inhibitors,
ARBs, and diuretics, thereby enhancing their
antihypertensive effects.
- is contraindicated in pregnancy
Inhibition of the renin-angiotensin system with ACE
inhibitors or ARBs may be incomplete because the
drugs disrupt the negative feedback action of ANG II on
renin release and thereby increase plasma renin activity
For these reasons, aliskiren has been used in
combination with an ACE inhibitor or ARB. However,
such dual blockade may not produce significant clinical
benefit and may be associated with adverse effects.
Other antihypertensive drugs, notably
hydrochlorothiazide and other diuretics, also increase
plasma renin activity.
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS
● decrease systemic vascular resistance without
increasing heart rate and promote natriuresis.
● they are effective in the treatment of
○ hypertension,
○ decrease morbidity and mortality in
heart failure and left ventricular
dysfunction after myocardial infarction
○ delay the progression of diabetic
nephropathy.
○ inhibit the degradation of bradykinin,
substance P, and enkephalins.
The action of ACE inhibitors to inhibit bradykinin
metabolism contributes significantly to their hypotensive
action.
Bradykinin is apparently responsible for some adverse
side effects, including cough and angioedema. These
drugs are contraindicated in pregnancy because they
cause fetal kidney damage.
ANGIOTENSIN RECEPTOR BLOCKERS
● Losartan, valsartan, and several others are
orally active, potent, and specific competitive
antagonists at angiotensin AT1 receptors.
○ The efficacy of these drugs in
hypertension is similar to that of ACE
inhibitors, but they are associated with a
lower incidence of cough.
● slow the progression of diabetic nephropathy.
● The antagonists are also effective in the
treatment of heart failure and provide a useful
alternative when ACE inhibitors are not well
tolerated
● generally well tolerated but should not be used
by patients with nondiabetic renal disease or
in pregnancy. In addition, some ARBs may
cause a syndrome known as sprue-like
enteropathy.
Valsartan has been reported to decrease the incidence
of diabetes in patients with impaired glucose tolerance.
I Marfan’s syndrome
- is a connective tissue disorder associated with
aortic disease and other abnormalities involving
increased transforming growth factor-β (TGF-β)
signaling. (blockade of the renin-angiotensin
system might be beneficial for this syndrome)
-
0
Tx: Atenolol - standard treatment; Losartan -
may be as effective as atenolol.
The clinical benefits of ARBs are similar to those of renin
and ACE inhibitors, and it is not clear if any has
significant advantages over the others.
KININS
BIOSYNTHESIS OF KININS
Kinins
- are potent vasodilator peptides
- formed enzymatically by the action of enzymes
known as kallikreins acting on protein
I
substrates called kininogens.
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 CHAPTER VI:INTRODUCTION TO AUTONOMIC PHARMACOLOGY
kallikrein-kinin system has several features in common
with the renin-angiotensin system.

KALLIKREINS
● are serine proteases present in plasma (plasma
kallikrein) and in several organs (tissue
kallikrein), including the kidneys, pancreas,
intestine, sweat glands, and salivary glands.
○ The two groups are secreted as
zymogens and are activated by
proteolytic cleavage.

○ The two groups differ in their gene

structure, molecular weight, substrate
specificity, and kinin produced.

● can convert prorenin to active renin, but the

physiologic significance of this action is not
known.

Plasma prekallikrein
- is activated by activated blood coagulation
factor XII (FXIIa). (Figure 17-4)

KININOGENS FORMATION & METABOLISM OF KININS

● the substrates for kallikreins and precursors of
kinin The pathway for the formation and metabolism of kinins
● present in plasma, lymph, and interstitial fluid. is shown in Figure 17–4.
● Two kininogens are present in plasma:
○ low-molecular-weight form (LMW The two major kinins in humans (present in plasma
kininogen) - crosses capillary walls and and urine):
serves as the substrate for tissue
kallikreins Bradykinin Lys-bradykinin or
○ high-molecular-weight form (HMW Kallidin
kininogen) - 15–20% of the total plasma
kininogen is in this form; is confined to ● is released from ● is released from
the bloodstream and serves as the HMW kininogen LMW kininogen
substrate for plasma kallikrein. by plasma by tissue
kallikrein kallikrein.
■ The two forms result from
differential splicing of the ● is the ● the major urinary
kininogen gene to generate predominant kinin form.
proteins that differ at the in plasma.
C-terminus. ● can be converted
● Involved in to bradykinin by
plasma an arginine
extravasation, aminopeptidase
bronchoconstricti
on, nociception,
vasodilation, and
inflammation

Kininases
- nonspecific exopeptidases or endopeptidases
- Rapidly metabolizes Kinin (half-life < 15
seconds)
- Two plasma kininases have been characterized:
Kininase I and Kininase II

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 CHAPTER VI:INTRODUCTION TO AUTONOMIC PHARMACOLOGY
Kininase I Kininase II
● synthesized in ● present in plasma
the liver and vascular
● is a endothelial cells
carboxypeptidase throughout the body.
that releases the
carboxyl terminal ● It is identical to
arginine residue. angiotensin-convertin
g enzyme (ACE,
peptidyl dipeptidase)
● inactivates kinins by
cleaving the carboxyl
terminal dipeptide
phenylalanyl-arginine
PHYSIOLOGIC & PATHOLOGIC EFFECTS OF KININS
Effects of Kinin in Organs
Organ Effect
Cardiovascular ● arteriolar or vaso-dilation
System ○ result from a direct
inhibitory effect of
kinins on arteriolar
smooth muscle
○ may be mediated by
the release of nitric
oxide or vasodilator
prostaglandins such
as PGE2 and PGI2
● Contraction in veins
○ Result from direct
stimulation of venous
smooth muscle or
○ From release of
vasoconstrictor
prostaglandins such
as PGE 2a.
● Contraction in the visceral
smooth muscle.
Endocrine and ● Modulate tone of salivary and
Exocrine pancreatic ducts.
Glands ● help regulate gastrointestinal
motility
● Influence the transepithelial
transport of water,
Yes
electrolytes, glucose, and
amino acids.
● regulate the transport of
water, electrolytes, glucose,
and amino acids in the
gastrointestinal tract and
kidney
● Activation of certain
prohormones, including
proinsulin and prorenin.
As noted earlier, prekallikreins and
kallikrein are present in several
glands, including the pancreas,
kidney, intestine, salivary glands, and
sweat glands, and they can be
released into the secretory fluids of
these glands.
EFFECTS ON CARDIOVASCULAR SYSTEM
When injected intravenously, kinins produce a rapid
but brief fall in blood pressure that is due to their
arteriolar vasodilator action.
● Intravenous infusions of the peptide fail to
produce a sustained decrease in blood
pressure;
● prolonged hypotension can only be produced by
progressively increasing the rate of infusion.
○ The rapid reversibility of the hypotensive
response to kinins is due primarily to
reflex increases in heart rate,
myocardial contractility, and cardiac
output.
Bradykinin
- produces a biphasic change in blood
pressure—an initial hypotensive response
followed by an increase above the preinjection
level.
- increases blood pressure when injected into the
central nervous system, but the physiologic
significance of this effect is not clear, since it is
unlikely that kinins cross the blood-brain barrier
The increase in blood pressure may be due to a reflex
activation of the sympathetic nervous system, but under
some conditions, bradykinin can directly release
catecholamines from the adrenal medulla and stimulate
sympathetic ganglia. (Note, however, that bradykinin can
increase the permeability of the blood-brain barrier to
some other substances.) Kinins have no consistent
effect on sympathetic or parasympathetic nerve endings.
aArteriolar dilation produced by kinins causes an
increase in pressure and flow in the capillary bed
● This effect may be facilitated by increased
capillary permeability
○ resulting from
■ contraction of endothelial cells
■ widening of intercellular
junctions
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 CHAPTER VI:INTRODUCTION TO AUTONOMIC PHARMACOLOGY
■ increased venous pressure KININ RECEPTORS & MECHANISM OF ACTION
secondary to constriction of
veins. Note: B - Bradykinin
■ As a result of these changes,
water and solutes pass from the
EFFECTS OF KININ AGONIST TO RECEPTORS
blood to the extracellular fluid,
lymph flow increases, and
B1 Receptor B2 receptor
edema may result.
● Has very limited
Endogenous Kinins do not appear to participate in the distribution in ● calcium
control of blood pressure under resting conditions but mammalian tissues mobilization
may play a role in postexercise hypotension. ● Have a few known ● chloride transport,
functional roles. ● formation of nitric
ROLE IN INFLAMMATION & PAIN ● participate in oxide
inflammatory ● activation of
Bradykinin has long been known to produce the four response, phospholipase C,
classic symptoms of inflammation—redness, local heat, ● May also be phospholipase A2,
swelling, and pain. important in the and adenylyl
long-lasting effect cyclase.
Kinins are rapidly generated after tissue injury and play of Kinin such as
a pivotal role in the development and maintenance of collagen synthesis
these inflammatory processes. and cell
multiplication.
Kinins are potent pain-producing substances when
applied to a blister base or injected intradermally. They
elicit pain by stimulating nociceptive afferents in the Bradykinin displays the highest affinity in most B2
skin and viscera. receptor systems, followed by Lys-bradykinin. One
exception is the B2 receptor that mediates contraction of
ROLE IN HEREDITARY ANGIOEDEMA venous smooth muscle; this appears to be more
sensitive to Lys-bradykinin.
X Hereditary angioedema F
- is a rare autosomal dominant disorder that DRUGS AFFECTING THE KALLIKREIN-KININ
results from deficiency or dysfunction of the C1 SYSTEM
esterase inhibitor (C1-INH).
- can be treated with drugs that inhibit the ● Peptides
formation or actions of bradykinin ● Icatibant

C1 esterase inhibitor (C1-INH) Icatibant

● a major inhibitor of proteases of the
complement, coagulation, and kallikrein-kinin
systems.
● deficiency results in:
○ activation of kallikrein
○ increased formation of bradykinin,
■ which by increasing vascular
permeability and other actions,
causes recurrent episodes of
angioedema of the airways,
gastrointestinal tract,
extremities, and genitalia
OTHER EFFECTS
There is evidence that bradykinin may play a beneficial,
protective role in certain cardiovascular diseases and
ischemic stroke-induced brain injury. On the other hand,
it has been implicated in cancer and some central
nervous system diseases
- is a second-generation B2 receptor antagonist.
- It is a decapeptide with an affinity for the B2
receptor similar to that of bradykinin and is
absorbed rapidly after subcutaneous
administration.
- effective in the treatment of hereditary
angioedema.
- Also useful in other conditions including
drug-induced angioedema, airway disease,
thermal injury, ascites, and pancreatitis.
FR 173657, FR 172357, and NPC 18884
- A third generation of B2-receptor antagonists
has been developed.
- These antagonists block both human and animal
B2 receptors and are orally active.
- They have been reported to inhibit bradykinin
induced bronchoconstriction in guinea pigs,
carrageenan-induced inflammation in rats, and
capsaicin-induced nociception in mice.

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 CHAPTER VI:INTRODUCTION TO AUTONOMIC PHARMACOLOGY
- These antagonists have promise for the
treatment of inflammatory pain in humans.
SSR240612
- is a new, potent, and orally active selective
antagonist of B1 receptors in humans and
several animal species.
- reduces obesity in diabetic rats, has analgesic
and anti-inflammatory activities in mice and rats,
and is currently in preclinical development for
the treatment of inflammatory and neurogenic
pain.
Inhibition of Kinin Synthesis:
● kallikrein inhibitor aprotinin
● C1-INH,
● cinryze
● Berinert
○ These are used for the intravenous
prophylaxis or treatment of hereditary
angioedema.
● Ecallantide (more potent and selective than
C1-INH and can be administered by
subcutaneous injection)
Actions of kinins mediated by prostaglandin generation
can be blocked nonspecifically with inhibitors of
prostaglandin synthesis such as aspirin.
ACE inhibitors
- enhances the actions of Kinins.
- block the degradation of the peptides. Indeed,
as noted above, inhibition of bradykinin
metabolism by ACE inhibitors contributes
significantly to their antihypertensive action.
These drugs have potential for the treatment of
hypertension, myocardial hypertrophy, and other
diseases.
VASOPRESSIN
Vasopressin (arginine vasopressin, AVP; antidiuretic
hormone, ADH)
- plays an important role in the long-term control
of blood pressure through its action on the
kidney to increase water reabsorption.
arginine vasopressin
- Regulates arterial pressure by its
vasoconstrictor action.
- Increases total peripheral resistance when
infused in doses less than those required to
produce maximum urine concentration.
AVP increases total peripheral resistance when infused
in doses less than those required to produce maximum
urine concentration. Such doses do not normally
increase arterial pressure because the vasopressor
activity of the peptide is buffered by a reflex decrease in
cardiac output.
When the influence of this reflex is removed, eg, in
shock, pressor sensitivity to AVP is greatly increased.
Pressor sensitivity to AVP is also enhanced in patients
with idiopathic orthostatic hypotension. Higher doses of
AVP increase blood pressure even when baroreceptor
reflexes are intact.
VASOPRESSIN RECEPTORS, AGONISTS, &
ANTAGONISTS
Three subtypes of AVP receptors have been identified;
all are G protein-coupled.
● V1a receptors
○ mediate the vasoconstrictor action of
AVP;
○ effects are mediated by Gq activation of
phospholipase C, formation of inositol
trisphosphate, and increased
intracellular calcium concentration
○ Agonists:
■ Vasotocin
■ vasopressin, or selepressin
(newer short-acting selective
V1a receptor agonist)
● V1b receptors mediate release of ACTH by
pituitary corticotropes.
● V2 receptors
○ mediate the antidiuretic action.
○ effects are mediated by Gs activation of
adenylyl cyclase.
○ Antidiuretics Analogs:
■ 1-deamino arginine vasopressin
(dDAVP)
■ 1-deamino arginine vasopressin
(dVDAVP).
AVP, often in combination with norepinephrine, has
proved beneficial in the treatment of septic and other
vasodilatory shock states, at least in part by virtue of its
V1a agonist activity.
Terlipressin (triglycyl lysine vasopressin)
- a synthetic vasopressin analog that is converted
to lysine vasopressin in the body, is also
effective.
V1a antagonists
- useful in revealing the important role that AVP
plays in blood pressure regulation in situations
such as dehydration and hemorrhage.
- Tx: Raynaud’s disease, hypertension, heart
failure, brain edema, motion sickness, cancer,
preterm labor, and anger management.
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 CHAPTER VI:INTRODUCTION TO AUTONOMIC PHARMACOLOGY
To date, most studies have focused on heart failure;
promising results have been obtained with
V2 antagonists (Tolvaptan)
- currently approved only for use in hyponatremia.
V1a antagonists also have potential, and
Conivaptan
- a drug with both V1a and V2 antagonist activity,
has also been approved for the treatment of
hyponatremia.
NATRIURETIC PEPTIDES
SYNTHESIS & STRUCTURE
Atrial ● Synthesized in
Natriuretic ○ Cardiac muscle
Peptide ○ Ventricular
(ANP) myocardium (by
neurons in the central
and peripheral
nervous system and
in the lungs)
○
● Structure
○ Derived from the
carboxyl end of a
common precursor
termed preproANP.
● Stimulus of (increased)
release:
○ Atrial stretch in the
heart via
mechanosensitive ion
channels.
○ Changing from
standing to supine
position and exercise
○ volume expansion
○ Sympathetic
stimulation via α1A
adrenoceptors,
endothelin via 𝐸𝑇𝐴
receptor subtype,
glucocorticoid, and
atrial vasopressin.
○ Plasma ANP
concentration
increases during
pathologic states:
■ Heart failure
■ primary
aldosteronism
■ chronic renal
failure
■ inappropriate
ADH
secretion
syndrome.
● Effects:
○ Vasodilation
○ Decrease Arterial
blood pressure
○ Inhibits release of
renin, aldosterone,
and AVP.
○ Increase sodium
excretion and urine
flow.
Brain ● Synthesized in
Natriuretic ○ Heart
Peptide ● Effects/role:
(BNP) ○ Exhibits natriuretic,
diuretic, and
hypotensive activities
(similar to those of
ANP but circulates at
a lower concentration)
C-type ● Located/ synthesized in
Natriuretic ○ central nervous
Peptide system
(CNP) ○ vascular endothelium,
○ Kidneys
○ intestine.
● Effects/role:
○ Potent vasodilator
○ Regulates peripheral
resistance
Urodilatin ● Synthesized in
○ Distal tubule of the
kidney (by alternative
processing of the
ANO precursor)
● Effects/role:
○ Paracrine regulator of
sodium and water
excretion (Potent
natriuresis and
diuresis)
○ Relaxes vascular
smooth muscle
PHARMACODYNAMICS & PHARMACOKINETICS
Three Natriuretic Peptide Receptor Subtypes:
NPR-A (ANP-A) ● Contain guanylyl
cyclase at the
intracellular
domain.
● Primary ligands:
ANP and BNP

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 CHAPTER VI:INTRODUCTION TO AUTONOMIC PHARMACOLOGY
NPR-B (ANP-B) ● Contain guanylyl
cyclase at the
intracellular
domain.
● Primary ligands:
CNP
NPR-C (ANP-C) ● May be coupled
with adenylyl
cyclase or
phospholipase C
● Binds to all three
natriuretics: ANP,
BNP, and CNP.
Neutral endopeptidase NEP 24.11 (neprilysin)
- Metabolizes the natriuretic peptide in the kidney,
liver, and lungs.
- Inhibition of this endopeptidase results in
increases in circulating levels of the natriuretic
peptides, natriuresis, and diuresis.
The peptides are also removed from the circulation by
binding to ANP-C receptors in the vascular
endothelium. This receptor binds the natriuretic peptides
with equal affinity. The receptor and bound peptide are
internalized, the peptide is degraded enzymatically, and
the receptor is returned to the cell surface.
Patients with heart failure have high plasma levels of
ANP and BNP; the latter has emerged as a diagnostic
and prognostic marker in this condition.
CLINICAL ROLE OF NATRIURETIC PEPTIDES
Natriuretic peptides may be administered as
● recombinant ANP (carperitide),
● recombinant BNP (nesiritide), or
● ularitide, the synthetic form of urodilatin
● These peptides produce vasodilation
and natriuresis
● have been investigated for the treatment
of congestive heart failure.
Nesiritide
- is approved for the treatment of decompensated
acute heart failure.
Ularitide
- has demonstrated beneficial effects in animal
models of heart failure and in phase 1 and 2
studies in heart failure patients.
- It is in phase 3 development as an infusion
treatment for acute decompensated heart
failure.
Increased Natriuretic Peptides
● Can be results of:
○ increased due to drugs that inhibit their
breakdown by neprilysin (NEP 24.11).
● The resulting increase in ANP and BNP
○ causes natriuresis and vasodilation,
as well as a compensatory increase in
renin secretion and plasma ANG II
levels. Because of the increase in ANG
II, these drugs are not effective as
monotherapy in the treatment of heart
failure.
However, they led to the development of drugs that
combine neprilysin inhibition with an ACE inhibitor in
order to prevent the increase in plasma ANG II, or with
an ARB to block the actions of ANG II.
Vasopeptidase inhibitors
● Drugs that combine neprilysin inhibition with
ACE inhibition. This includes:
○ Omapatrilat
■ lowers Blood Pressure in animal
models and patients with
hypertension and improves
cardiac function with heart
failure.
■ Adverse effects: significance
incidence of angioedema and
cough. (as a result of decreased
metabolism of bradykinin)
■ NOT APPROVED FOR
CLINICAL USE
○ Sampatrilat
○ fasidotrilat.
● The combination of an ANG II receptor
antagonist with a neprilysin inhibitor (ARNI)
increases endogenous natriuretic peptide levels
while simultaneously blocking the effects of the
increase in plasma ANG II.
LCZ696
- is a single molecule composed of the neprilysin
inhibitor prodrug sacubitril and the ANG II
receptor antagonist valsartan.
- marketed as Entresto, is approved by the US
Food and Drug Administration
- In healthy subjects, LCZ696 increased plasma
ANP and cGMP levels in combination with
increases in plasma renin and ANG II levels.
● Clinical trials in patients with heart failure
demonstrated many beneficial effects of
LCZ696, and it was superior to ACE inhibition or
angiotensin receptor blockade in reducing the
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risk of death and hospitalization from heart
○ Enzymatic degradation by
failure.
NEP 24.11 (neprilysin) and
● Side effects:
by 𝐸𝑇𝐵 𝑟𝑒𝑐𝑒𝑝𝑡𝑜𝑟
○ hypotension,
○ hyperkalemia,
○ renal impairment,
○ angioedema ET-3 ● Biosynthesis:
○ found in highest
ENDOTHELINS concentration in the brain
but is also found in the
- Is the source of a variety of substances with gastrointestinal tract,
vasodilator (nitric oxide and PGI2) and lungs, and kidneys.
vasoconstrictor activities. ● Structure:
○ Is a 21-amino-acid peptide
BIOSYNTHESIS, STRUCTURE, & CLEARANCE containing two disulfide
bridges.
Three Isoforms of Endothelin: ● Clearance:
○ Enzymatic degradation by
NEP 24.11 (neprilysin) and
ET-1 ● Biosynthesis by 𝐸𝑇𝐵 𝑟𝑒𝑐𝑒𝑝𝑡𝑜𝑟
○ predominantly secreted by
the vascular endothelium;
○ produced by neurons and ETs are present in the blood in low concentration; they
astrocytes in the central apparently act locally in a paracrine or autocrine fashion
nervous system and in rather than as circulating hormones.
endometrial, renal
mesangial, sertoli, breast the autocrine factors act on the cells which produce
epithelial, and other cells. them whereas the paracrine factors act on the cells that
● Structure: are in close proximity to the cells that produce them
○ Is a 21-amino-acid peptide
containing two disulfide ACTIONS
bridges.
○ Its gene expression is 𝐸𝑇𝐴𝑟𝑒𝑐𝑒𝑝𝑡𝑜𝑟𝑠
increased by growth
- Have high affinity to ET-1 and low affinity to
factors and cytokines,
ET-3.
including TGF-β and
- Located in the smooth muscle cells
interleukin I (IL-I),
- Mediate vasoconstriction.
vasoactive substances
including ANG II and AVP
𝐸𝑇𝐵𝑟𝑒𝑐𝑒𝑝𝑡𝑜𝑟𝑠
and mechanical stress.
■ Although, its ● Equal affinities to ET-1 and ET-3.
expression is ● Located on the
inhibited by nitric ○ vascular epithelial cells
oxide, prostacyclin, ■ Mediate release of nitric oxide,
and ANP. and PGI2
● Clearance: ○ Smooth Muscle Cells
○ Enzymatic degradation by ■ Mediate vasoconstriction.
NEP 24.11 (neprilysin) and
by 𝐸𝑇𝐵 𝑟𝑒𝑐𝑒𝑝𝑡𝑜𝑟 Both receptors belong to the G protein-coupled
seven-transmembrane domain family of receptors.
ET-2 ● Biosynthesis:
○ produced predominantly in ET’S ACTION:
the kidneys and intestines ● cause potent dose-dependent vasoconstriction
● Structure: in most vascular beds.
○ Is a 21-amino-acid peptide ● When administered intravenously, it causes a
containing two disulfide rapid and transient decrease in arterial blood
bridges. pressure followed by a sustained increase.
● Clearance: ○ The depressor response results from
the release of prostacyclin and nitric
oxide from the vascular endothelium.

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○ The pressor response results from the The activity of the system is higher in males than in
direct contraction of the vascular smooth females. It increases with age, an effect that can be
muscle counteracted by regular aerobic exercise.

Increased production of ET-1 has been implicated in a

ET’s ACTIONS ON ORGANS
variety of diseases, including pulmonary and arterial
hypertension, renal disease, diabetes, cancer, heart
Heart ● Exerts positive Inotropic and
failure, and atherosclerosis.
chronotropic actions.
● Are potent coronary vascular
Endothelin Antagonist
contractors.
● with bosentan, ambrisentan, and macitentan has
Kidneys ● Vasoconstriction proved to be an effective and generally
● Decrease glomerular filtration well-tolerated treatment for patients with
rate and sodium and water pulmonary arterial hypertension.
secretion. ● Side effect: Hypertoxicity - but is dose-related
and reversible.
Respiratory ● Cause potent contraction of ● Occasionally cause systemic hypotension,
system tracheal and bronchial smooth increased heart rate, facial flushing or edema,
muscle and headaches.
● Potential gastrointestinal effects include nausea,
Endocrine ● Increase secretion of renin, vomiting, and constipation.
system aldosterone, AVP, and ANP ● Which are reasons that it is contraindicated in
pregnant women.
.
INHIBITION OF ENDOTHELIN SYNTHESIS Other promising targets for these drugs are resistant
& ACTION hypertension, chronic renal disease, connective tissue
disease, and subarachnoid hemorrhage.
Bosentan
- A nonselective ET receptor antagonist.
DUAL INHIBITORS OF ENDOTHELIN-CONVERTING
- Active orally and blocks both the initial transient
depressor (𝐸𝑇𝐵) and the prolonged pressor (𝐸𝑇𝐴) ENZYME AND NEPRILYSIN
response to intravenous ET.
- Macitentan - developed by modifying the structure of Daglutril (SLV306)
bosentan. ● is a prodrug that is converted to the active
metabolite KC-12625, a mixed inhibitor of
Ambrisentan endothelin converting enzyme and neprilysin.
- 𝐸𝑇𝐴 antagonist. Thus, it simultaneously inhibits the formation of
ET and the breakdown of natriuretic peptides
Sitaxsetan
- Most 𝐸𝑇𝐴.selective antagonist. ● appears to be well tolerated with few or none of
the side effects on liver function and edema
Phosphoramidon observed with endothelin antagonists.
- Blocks formation of ETs by inhibiting endothelin
converting enzymes.
● It has been shown to have beneficial effects in
- is not specific for endothelin-converting enzyme, but heart failure and to lower blood pressure in
more selective inhibitors including CGS35066 are patients with type 2 diabetes and nephropathy
available
VASOACTIVE INTESTINAL PEPTIDE
PHYSIOLOGIC AND PATHOLOGIC ROLES OF ● is a 28-amino-acid peptide that belongs to the
ENDOTHELINS glucagon-secretin family of peptides.

EFFECTS OF ENDOTHELINS ANTAGONISTS ● Effects are mediated by G protein-coupled

● Systemic Administration receptors, VPAC1 and VPAC2.
○ Vasodilation ○ Both receptors are widely distributed in
○ Decrease arterial pressure. the central nervous system and in the
● Intra-arterial administration heart, blood vessels, and other tissues.
○ Slow-onset vasodilation
● Location:
○ is widely distributed in the central and
peripheral nervous systems, where it

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 CHAPTER VI:INTRODUCTION TO AUTONOMIC PHARMACOLOGY
functions as one of the major peptide
neurotransmitters.
○ Present in cholinergic presynaptic
neurons in the central nervous system
and in peripheral peptidergic nerves
innervating diverse tissues including the
heart, lungs, gastrointestinal and
urogenital tracts, skin, eyes, ovaries,
and thyroid gland.
○ also present in key organs of the
immune system including the thymus,
spleen, and lymph nodes
● Action:
○ Cardiovascular System
■ Vasodilation in most vascular
beds and in this regard makes
them more potent on a molar
basis than Acetylcholine.
○ Heart
■ Coronary vasodilation
■ Exert positive inotropic and
chronotropic effects.
Binding of VIP to its receptors results in activation of
adenylyl cyclase and formation of cAMP, which is
responsible for the vasodilation and many other effects
of the peptide.
VIP has potential for the treatment of systemic and
pulmonary hypertension and heart failure, but this is
limited by its short half-life in the circulation.
Vasomera
- stable long-acting form of VIP that is selective
for VPAC2 receptors
- reduces blood pressure in animal models of
hypertension and heart failure and has been
shown to be safe and well tolerated after single
subcutaneous or intravenous injection in phase
1 studies in patients with essential hypertension
SUBSTANCE P
● Effects/Actions:
○ exerts a variety of central actions that
implicate the peptide in behavior,
anxiety, depression, nausea, and
emesis.
○ arteriolar vasodilator - mediated by
release of nitric oxide from the
endothelium.
○ contraction of venous, intestinal, and
bronchial smooth muscle.
○ stimulates secretion by the salivary
glands and causes diuresis and
natriuresis by the kidneys
The actions of substance P and neurokinin A and B are
mediated by three Gq protein-coupled tachykinin
receptors designated NK1, NK2, and NK3.
NK1
- Widespread throughout the body.
- Most of the central and peripheral effects of
substance P are mediated by this receptor.
Several nonpeptide NK1 receptor antagonists have
been developed. These compounds are highly selective
and orally active, and enter the brain.
- may be useful in treating depression and other
disorders and in preventing
chemotherapy-induced emesis.
NEUROTENSIN
● Is synthesized as a large precursor that also
contains Neuromedin N (A six-amino acid
NT-like peptide.)
● Most of its activity is mediated by the last six
amino acids, NT (8-13)
● NTR1 has a higher affinity for NT than NTR2
and is the major mediator of the diverse effects
of NT.
In the gut, processing leads mainly to the formation of
NT and a larger peptide that contains the neuromedin N
sequence at the carboxyl terminal.
Both peptides are secreted into the circulation after
ingestion of food.
● Has dual function: Neurotransmitter and
neuromodulator, in the central nervous system
and as a local hormone in the periphery.
● Administration site effect:
○ Central Nervous system:
■ hypothermia,
■ antinociception
■ modulation of dopamine and
glutamate neurotransmission
○ Peripheral Nervous System
■ vasodilation,
■ hypotension,
■ tachycardia,
■ increased vascular permeability,
■ increased secretion of several
anterior pituitary hormones,
■ hyperglycemia,
■ inhibition of gastric acid and
pepsin secretion
■ inhibition of gastric motility
In the central nervous system, there are close
associations between NT and dopamine systems, and
NT may be involved in clinical disorders involving
dopamine pathways such as schizophrenia, Parkinson’s
disease, and drug abuse.
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The effects of NT are mediated by three subtypes of NT
receptors, designated NTR1, NTR2, and NTR3, also
known as NTS1, NTS2, and NTS3.
The potential use of NT as an antipsychotic agent has
been hampered by its rapid degradation in the circulation
and inability to cross the blood-brain barrier. Although
they may also be useful in the treatment of pain,
psychostimulant abuse, and Parkinson’s disease.
Potential adverse effects include hypothermia and
hypotension
SR142948A - is a potent antagonist of the hypothermia
and analgesia produced by centrally administered NT.
CALCITONIN GENE-RELATED PEPTIDE
● Consist 37 amino-acids.
● Exists in two forms: α-CGRP and β-CGRP,
which are derived from separate genes and
differ by three amino acids but exhibit similar
biological activity.
● present in large quantities in the C cells of the
thyroid gland. It is also distributed widely in the
central and peripheral nervous systems,
cardiovascular and respiratory systems, and
gastrointestinal tract.
● Effects:
○ Central nervous system
■ Hypertension
■ Suppression of feeding
○ Systemic Circulation
■ Hypertension
■ tachycardia
serotonin agonist normalizes cranial CGRP
levels.
ADRENOMEDULLIN
● Consists of 52-amino acids.
● Located:
○ (highest concentrations) adrenal glands,
hypothalamus, and anterior pituitary
○ (high levels are also present) kidneys,
lungs, cardiovascular system, and
gastrointestinal tract.
○ Plasma (apparently originates in the
heart and vasculature.)
● Effects:
○ In animals, it dilates resistance
vessels in the kidney, brain, lungs, hind
limbs and mesentery.
■ Results in a marked long-lasting
hypotension. Thus, causing
reflex increase in heart rate and
cardiac output (as the body’s
way of compensating for the low
pressure).
■ Also occurs in healthy humans
during intravenous infusion of
the peptide.
○ Increase sodium excretion and renin
release in the Kidney
○ exerts other endocrine effects including
inhibition of aldosterone and insulin
secretion.
○ Increases AM during intense exercise.
Binding of AM to CLR activates Gs and triggers cAMP
formation in vascular smooth muscle cells, and
increases nitric oxide production in endothelial cells.

The actions of CGRP are mediated via a single receptor NEUROPEPTIDE Y

type. This heterodimeric receptor consists of the G ● consisting of three polypeptide agonists that
protein-coupled calcitonin receptor-like receptor (CLR) bind and activate four distinct receptors with
combined with the receptor activity-modifying protein different affinity and potency. Each of these
RAMP1 peptides have 36-amino acids

Nonpeptide CGRP receptor antagonists

Pancreatic ● Synthesis:
● Has been recently developed together with
polypeptide ○ ecreted in Iislets
peptide antagonist of the CGRP
(PP) of Langhans after
● targets the interface between CLR and RAMP1
food ingestion in
and thereby makes them more selective for the
proportion to the
CGRP receptor.
caloric content.
● Examples:
● Action:
○ olcegepant
○ Acts mainly in the
■ Effective tx of migraine but have
brainstem and
low bioavailability so it must be
vagus to promote
administered intravenously.
appetite
○ telcagepant
suppression.
○ Inhibit gastric
Peptide CGRP receptor antagonists
emptying.
- Are released during migraine attacks and
○ Increase energy
successful treatment of migraine with a selective

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- Y1 and Y2 receptors are of major importance in
expenditure.
the cardiovascular and other peripheral effects
○ Exerts direct
of the peptide.
action in the lungs
- Y4 receptors have a high affinity for pancreatic
Peptide YY ● Synthesis
polypeptide and may be a receptor for the
(PYY) ○ released by
pancreatic peptide rather than for NPY.
entero-endocrine
L cells of the distal
- Y5 receptors are found mainly in the central
gut in proportion
nervous system and may be involved in the
to food intake
control of food intake
● Action
- Antiobesity Agent
○ produces
anorexigenic
UROTENSIN
effects.
● An 11 amino acid peptide
Neuropeptide Y ● Synthesis/Location
(NPY) ○ Abundant ● Originally identified as a fish, but isoforms are
neuropeptide in known to be present in the human and other
central and mammalian species.
peripheral nervous
system ● Effects:
● Action ○ In vitro, poten constrictor of vascular
○ Acts as a smooth muscle.
neurotransmitter ■ Although its activity depends on
○ Localized in the type of blood vessel and the
noradrenergic species from which the vessel
neurons (fx: was obtained.
Vasoconstrictor
and cotransmitter ○ In vivo, UII has complex hemodynamic
with effects, the most prominent being
norepinephrine. regional vasoconstriction and cardiac
depression.
● Effects: Central Nervous
system ○ Cardiovascular system (Other Effects)
○ increased feeding, ■ exerts osmoregulatory actions,
hypotension, induces collagen and fibronectin
hypothermia, accumulation, modulates the
respiratory inflammatory response, and
depression, and inhibits glucose-induced insulin
activation of the release.
hypothalamic-pitui
tary-adrenal axis. ● Location: (of major expression in humans)
○ Other effects: ○ central nervous system, cardiovascular
vasoconstriction of system, lungs, liver, and endocrine
cerebral blood glands including the pituitary, pancreas,
vessels, positive and adrenal.
chronotropic and ○ UII is also present in plasma, and
inotropic actions potential sources of this circulating
on the heart, and peptide include the heart, lungs, liver,
hypertension and kidneys.
UT Receptors
- are widely distributed in the brain, spinal cord,
heart, vascular smooth muscle, skeletal muscle,
The diverse effects of NPY (and PP and PYY) are and pancreas.
mediated by four subtypes of NPY receptors designated - UII binds to this receptor and cause:
Y1, Y2, Y4, and Y5. - Vasoconstriction (which is mediated by
- All are Gi protein-coupled receptors linked to by the phospholipase C, inositol
mobilization of Ca2+ and inhibition of adenylyl trisphosphate, diacylglycerol signal
cyclase. transduction pathway)

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Natriuretic ● Vasodilation ● Recombinant

Urantide (“urotensin antagonist peptide”)
Peptides ● Natriuresis/ NPs:
- is a penicillaminesubstituted derivative of UII.
Diuresis Carperitide
● Inhibition of (ANP),
Palosuran
RAAS Nesiritide
- is an orally active nonpeptide antagonist of the
(BNP)
UII receptor.
● Vasopeptidas
- has displayed beneficial effects in animal models
e inhibitors
of renal failure but not in hypertensive patients
(Omapatrilat,
with type 2 diabetic nephropathy
Sampatrilat,
Fasidotrilat)
Ligand/Recept Effect Drugs
or Endothelin ● Vasodilation ● Bosentan (ETA
and ETB
Renin ● Converts ● Aliskiren (inh) receptor
ANG1 to antagonist -
ANG2 nonselective)
● Macitentan
Angiotensin ● Hypertension ● Angiotensin (ETA and ETB
● Aldosterone Converting receptor
release Enzyme antagonist -
● ADH release Inhibitors nonselective)
● Inhibits Renin (-pril) ● Sitaxsentan,
release ● Angiotensin ambrisentan
● Mitogenic Receptor (ETA receptor
(cardiovascula Blockers antagonists)
r hypertrophy) (-sartan)
Vasoactive ● Vasodilation ● Vasomera
Intestinal ● Multiple (VPAC2
Angiotensin ● Vasoconstricti ● Angiotensin Peptide metabolic, receptor
Receptor Type 1 on Receptor endocrine, and agonist -
Blockers other effects selective)
(-sartan)
Substance P ● Vasodilation ● Aprepitant
Angiotensin ● Vasodilation ● Angiotensin (tachykinin
Receptor Type 2 Receptor NK1 receptor
Blockers antagonist)
(-sartan)
Neurotensin ● Interacts with
Kinins ● Rapid ● Icatibant dopamine
Vasodilation (antagonist) system
● Edema ● Kinin
● Inflammation synthesis Calcitonin ● Blocks central ● Telcagepant
(redness, inhibitors Gene-Related and peripheral (CGRP
swelling, pain, (Aprotinin, Peptide (vasodilator) receptor
local heat) Cinryze, actions of antagonist)
Berinert, CGRP ● Olcegepant
Ecallantide) (CGRP
receptor
Vasopressin ● Increase water ● Terlipressin antagonist)
(ADH) reabsorption (V1a agonist)
(V2) ● Reclovaptan
● Vasoconstricti (V1a
on (V1a) antagonist)
● ACTH release ● Tolvaptan (V2
(V1b) antagonist)
● Conivaptan
(V1a and V2
antagonist)

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