Vasoactive Peptides
State-of-the-Art Review
SAMI I. SAID,
M.D.
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
SUMMARY At least 16 naturally occurring peptides either constrict or dilate blood vessels. Many of
these peptides are present in nerve cells and nerve terminals supplying systemic and pulmonary blood
vessels and the heart. Such neuropeptides are released locally as neurotransmitters, and can influence
vascular tone, local and regional blood flow, arterial blood pressure, and cardiac function. There is
evidence for the participation of at least some vasoactive peptides in the regulation of these functions
and in the mediation or modulation of systemic shock and arterial hypertension. The investigation of
vasoactive peptides in relation to cardiovascular function and dysfunction is at a promising threshold.
(Hypertension 5 (supp I): M7-I-26, 1983)
KEY WORDS • vasopressor • vasodepressor
vasodilation • shock • hypertension
A
large number of biologically active peptides
have been isolated and characterized in recent
years. There is a growing conviction that
these peptides participate in the regulation of many
organ functions. Neuroscientists, endocrinologists,
and gastroenterologists have led other groups in recognizing the likely physiological and clinical significance of these peptides, most of which are found in the
brain and gut.1"1
Since many biologically active peptides are capable
of influencing vascular smooth muscle, and thus blood
flow and blood pressure, peptides with these vasoactive properties are reviewed here. Emphasis is placed
on the cardiovascular effects of the more recently identified peptides, with special reference to their possible
roles in the regulation of blood pressure in normal and
abnormal states. Bradykinin and angiotensins, which
are extensively reviewed elsewhere, are only briefly
mentioned here.
hypotension
* vasoconstriction
activity has generally been overshadowed by other actions of the peptide.
As will become apparent in the following para :
graphs, the ability to induce either vasodilation or vasoconstriction is shared by a variety of apparently unrelated peptides. It is possible in some instances,
however, t o ' recognize certain structural features
among these peptides that correlate with their vasodilator or vasoconstrictor activity. Such features will be
noted.
Angiotensins
Angiotensin II (table 1) is one of the most potent
systemic vasopressors known. Its formation from angiotensin I through the action of angiotensin-converting enzyme, the localization and properties of this enzyme, and the physiology, pathophysiology, and
pharmacology of the renin-angiotensin systems in the
body are topics of recent comprehensive reviews.5""
Bombesin
A 14-residue peptide (table 1) isolated from the skin
of the frog Bombina bombina, bombesin has spasmogenic activity on a variety of vascular and non-vascular
smooth muscle structures.12 It induces vasoconstriction and systemic hypertension in most animal species,
hypotension in monkeys, but neither in humans. A
mammalian counterpart of the amphibian peptide is the
27-residue gastrin-releasing peptide, which has been
found in the brain and gastrointestinal tract.13 Bombesin itself may also occur in human oat-cell cancer of
the lung. 1415
Biological Activity of Peptides
Which Peptides are Vasoactive?
Peptides with vasoactive properties are given in the
accompanying list (see box), which is not meant to be
complete. For some of these peptides (e.g., angiotensin II, bradykinin), vasoactivity is a dominant feature
of their biological actions; for others (e.g., prolactin,
parathyroid hormone), the pressor or vasodepressor
From the Department of Medicine, University of Oklahoma
Health Sciences Center and Veterans Administration Medical Center, Oklahoma City, Oklahoma.
Address for reprints: Sami I. Said, M.D., University of Oklahoma Health Sciences Center, P.O. Box 26307, Oklahoma City,
Oklahoma 73126.
Bradykinin
A potent systemic vasodilator and vasodepressor,
bradykinin (table 1) also increases systemic, but not
1-17
1982 BLOOD PRESSURE COUNCIL
1-18
I,
HYPERTENSION, VOL
5, No 2,
MARCH-APRIL
2. Bombesin
Bradykinin
Cholecystokinin-pancreozymin
Neurotensin
Opioid peptides
Oxytbcin
Parathyroid hormone
Prolactin
Sauvagine
Somatostatin
Substance P
Thyrotropin-releasing hormone
Urotensin
Vasoactive intestinal peptide
Vasopressjn
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
Opioid Peptides
The endogenous opioid peptides, including endorphins and enkephalins, have important effects on cardiovascular function. The specific effects in experimental animals depend on the individual peptide and
the method of its administration. Like morphine,
opioid peptides generally cause peripheral vasodilation
and a fall in arterial blood pressure, when given intravenously. 1920 Administered intracisternally in anesthetized dogs and rats, morphine, /3-endorphin, Dala2-met enkephalin and D-ala2-met-enkephalinamide
induce hypotension and bradycardia, while a-endorphin induces hypertension.21-22 Centrally administered, met-enkephalin is vasopressor in rats but ineffective in dogs.
pulmonary, microvascular permeability. The generation, inactivation, and biological role of bradykinin
have been intensely investigated in recent years.6
Cholecystokinin-Pancreozymin (CCK)
Originally thought to be limited to endocrine cells in
the gastrointestinal tract, CCK has also been found in
the brain, especially the cerebral cortex, and in peripheral nerves. In addition to stimulating gallbladder contraction and pancreatic enzyme secretion, it has distinct, though limited, vasoactive properties. The
peptide and its C-terminal octapeptide fragment induce
splanchnic vasodilation and mild hypotension in anesthetized dogs.16 l7 CCK is naturally present in several
molecular forms, including 4-, 8-, 33- and 39-residue
peptides.
Neurotensin
A 13-residue peptide (table 1), neurotensin is present in the central and peripheral nervous systems and
Oxytocin
One of the two "neurohypophyseal peptides"
(though actually secreted in the hypothalamic magnocellular nuclei), oxytocin has vasodepressor activity,
at least in birds. The ability of oxytocin to lower chicken blood pressure is the basis for a bioassay method for
this peptide.23
Parathyroid Hormone (PTH)
Bovine parathyroid hormone (1-34 fragment) produces dose-related arterial hypotension in dogs, rats
and other species. This action is not mediated by
adrenergic, cholinergic, or histamine receptors. 2 4 "
PTH exerts a direct vasodilator action in perfused rat
hindlimbs and in dog renal, hepatic, pancreatic and
coronary vascular beds; it also relaxes isolated strips of
rabbit aorta.24-M The vasodilator effect of PTH in dogs
is evident at doses that are too small (0.01 U/kg) to
cause hypercalcemia. Chemical manipulations of the
TABLE 1. Amino-Acid Sequences of Some Vasoactive Peptides
Peptide
Angiotensin I
Angiotensin II
Bradykinin
Substance P
Neurotensin
Somatostatin
Bombesin
Thyrotropin-releasing hormone
Oxytocin
Vasopressin
1983
gastrointestinal organs. It causes vasodilation, hypotension, peripheral cyanosis, and increased vascular
permeability in anesthetized rats. In dogs, however,
neurotensin is a systemic vasoconstrictor.18 The
chemically related amphibian peptide, xenopsin, is
also vasoactive.
Vasoactive Peptides
1. Angiotensin I and II
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
SUPP
Amino-acid sequence
H - Asp - Arg - Val - Tyr - He - His - Pro - Phe - His - Leu - OH
H - Asp - Arg - Val - Tyr - He - His - Pro - Phe - OH
H - Arg - Pro - Pro - Gly - Phe - Ser - Pro - Phe - Arg - OH
H - Arg - Pro - Lys - Pro - Gin - Gin - Phe - Phe - Gly - Leu - Met - NH2
pyroGlu - Leu - Tyr - Glu - Asn - Lys - Pro - Arg - Arg - Pro - Tyr - He - Leu OH
H-AIa-Gry-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-SerCys - OH
pyroGln - Arg - Leu - Gly - Asn - Gin - Trp - Ala - Val - Gly - His - Leu - Met OH
pyroGlu - His - Pro - NH2
H - Cys - Tyr - He - G|n - Asn - Cys - Pro - Leu - Gly - NH2
H - Cys - Tyr - Phe - Gin - Asn - Cys - Pro - Arg - Gly - NH2
VASOACTIVE PEPTlDES/Sa/rf
PTH molecule show that distinct and different parts of
the sequence are responsible for the hypercalcemic and
vasoactive properties.25 The occurrence of basic amino
acids in adjacent positions may be important to the
vasodilator activity of PTH." Other vasodilator peptides, including VIP and neurotensin, also possess adjacent basic residues.
Prolactin
Among the least widely known actions of prolactin
is its ability to influence vascular smooth muscle. In
low concentrations (0.6 /u.g/hr), acute or chronic administration of ovine prolactin raises blood pressure in
rabbits and rats and potentiates pressor responses of rat
mesenteric vessels to norepinephrine and angiotensin
II.26-27 Infusions of higher concentrations (8.9 Aig/hr)
of prolactin decrease blood pressure in rats.27
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
Sauvagine
Recently isolated from the skin of the frog Phyllomedusa sauvagei, sauvagine is a 40-residue peptide
with a long-lasting hypotensive activity in many species, including humans. 28 - N Sauvagine, structurally related to corticotropin-releasing factor, also has potent
endocrine effects, provoking the release of ACTH and
/3-endorphin from the pituitary.28-29
Soniatostatin
This hypothalamic tetradecapeptide (table 1), which
is also present in peripheral tissues, can influence vascular smooth muscle. Intravenous infusion of somatostatin (1 /xg/kg) in anesthetized human subjects reduced splanchnic blood flow (by up to 56%),
augmented external iliac blood flow (by 43%), and
raised mean arterial blood pressure (by 20%). w
Substance P
Widely distributed in the brain and in nerves supplying many organs, Substance P is an 11-residue peptide
with some structural similarities to bradykinin (table 1)
and major actions on the circulation. These actions
include peripheral vasodilation and transient systemic
hypotension.31 A related peptide, physalaemin, originally discovered in amphibian skin, has also been
found in mammalian tissues.
Thyrotropin-Releasing Hormone (TRH)
Injections of TRH (2 mg/kg) in awake rats cause an
increase in mean arterial blood pressure that persists
for 30 minutes.32 TRH (table 1) appears to antagonize
the cardiovascular effects of endogenous opiate peptides, which have overall vasodepressbr activity.32
Urotensin I
A 41-residue peptide recently isolated from the urophysis of a teleost fish, Catostomus commersoni; urotensin I is a selective dilator of mesenteric vessels in
mammals.33-34 It also induces hypotension and increases cardiac output in anesthetized dogs. 33 - M These
effects are not influenced by adrenergic, histaminergic, or muscarinic cholinergic blockade. Urotensin I
1-19
shows a striking sequence homology with ovine corticotropin-releasing factor and with sauvagine.33-M
Vasoactive Intestinal Peptide (VIP)
Originally isolated from porcine intestine, VIP has
subsequently been found in the brain and peripheral
nerves of all mammalian species and lower forms.35
t h e 28-residue peptide has potent vasodilator activity
in coronary, splanchnic, extremity, extracranial, and
other vascular beds.35 As a consequence of this generalized vasodilation, VIP induces systemic hypotension
(fig. I). 3 3 - x The vascular effects of VIP are independent of adrenergic or cholinergic receptors and, with the
exception of the vasodilation of pial vessels,37 are not
mediated by prostaglandin release. The related peptides, secretin and glucagon, have considerably
weaker activity on vascular and nonvascular smooth
muscle.
Vasopressin
The second of the neurohypophyseal peptides, vasopressin has pressor activity that was the basis for its
recognition and its given name. On a molar basis,
vasopressin is as potent as angiotensin II or norepinephrine in raising mean arterial blood pressure of
rats.38 Arginine-vasopressin (table 1) has equal pressor
and antidiuretic activities. Structural changes in the
molecule (e.g., deamination at Position 1, substitution
of a more lipophilic amino acid for Gin at Position 4,
and of D-for L-Arg at Position 8) have led to the
synthesis of peptides with enhanced antidiuretic, relative to pressor, activity.39 Thus, l-deamino-4 valine-8D arginine vasopressin has no detectable vasopressor
activity, but has four times the antidiuretic activity of
arginine-vasopressin. The latter compound also antagonizes the pressor response of arginine vasopressin.
Other substitutions have resulted in enhancement of
the pressor/antidiuretic activity. For example, 8-ornithine vasopressin has a pressor/antidiuretic activity
ratio of 4, and 2-phenylalanine-8-ornithine vasotocin
is the most highly selective pressor/antidiuretic agent
known to date, with a pressor/antidiuretic activity ratio
of 255. w As noted earlier, the closely related peptide
oxytocin is actually vasodepressor, at least in birds.23
Distribution of Vasoactive Peptides
Peptides Hormones and Neurotransmitters
Few of the vasoactive peptides (e.g., bombesln,
CCK, parathyroid hormone) are localized in endocrine
cells. Such peptides may function as hormones, acting
on remote target organs, or as locally active paracrine
secretions. On the other hand, most other peptides are
localized mainly in nerve cell bodies, nerve fibers and
nerve endings. These peptides, occurring in neurons of
the central and peripheral nervous systems, are known
as neuropeptides. Many are already known to exhibit
characteristic features of neurotransmitters, such as
concentration in nerve terminals and synaptosomes,
axonal transport, and release with depolarizing concentrations of K + in the presence of Ca 2 + .'
1-20
1982 BLOOD PRESSURE COUNCIL
SUPP
I,
HYPERTENSION, VOL
5, No 2,
MARCH-APRIL
1983
KX>-
fVI.P 3OOng/kg
l-asmln—|
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
FIGURE 1. Vasodilator and hypotensive effects of vasoactive-intestinal peptide (VIP) in anesthetized dog. Infusion of peptide (300
ng/kg) into a superficial branch of a femoral artery caused a greater than fivefold increase in femoral arterial blood flow (continuous
tracing), measured by an electromagnetic flow probe, and a 60 mm Hgfall in mean aortic blood pressure (interrupted tracing). The
infusion lasted 30 seconds (bar). Blood flow was still elevated 16 minutes after the infusion. (Reproduced from Said SI: Vasoactive
Intestinal Peptide. New York, Raven Press, 1982 with permission.)
Neuropeptides are. being increasingly recognized as
forming a third component of the autonomic nervous
system, the peptidergic system of nerves.m The existence of a nonadrenergic, noncholinergic nervous system has been demonstrated in many tissues and organs,
including blood vessels.41-43 The identity (or identities)
of the transmitters) of this system, sometimes also
known as the "purinergic" system, has been in dispute.41 Certain neuropeptides, especially VIP, are now
under investigation as the possible responsible
transmitters.44-45
The localization of vasoactive peptides in the central
nervous system is of special interest in relation to their
possible regulatory role. For example, neurons containing Substance P, VIP, and enkephalins innervate
cardiovascular centers in the nucleus tractus solitarius
and other nuclei;46 and norepinephrine-containing neurons innervate the large hypothalamic neuroendocrine
cells which secrete arginine vasopressin (see below).47
Co-Existence of Peptides and "Classical"
Neuro transmitters
Despite the earlier, widely propagated dictum of
"one neuron, one transmitter," recent evidence has
documented the frequent occurrence, in the same neurons, of more than one transmitter.48 These are usually
a peptide together with a catecholamine, acetylcholine, or serotonin. Examples of this coexistence (and
sometimes co-release) of peptides and other neurotransmitters are given in table 2.
Vasoactive Peptides and the Systemic Circulation
Peptides in Systemic Vessels
Immunohistochemical techniques have demonstrated the presence of some vasodilator peptides in nerve
fibers and nerve terminals within the walls of systemic
blood vessels. This distribution is best exemplified by
VIP and Substance P. VIP-containing nerves supply
vessels to the digestive organs, upper respiratory passages, tracheo-bronchial tree, skin, skeletal muscle,
brain, ocular and extracranial structures, genitourinary
system, adrenal gland, and other sites49"52 (fig. 2). Locally released, VIP is therefore well positioned to influence blood flow to individual organs, regional
blood flow, total peripheral vascular resistance, and
arterial blood pressure.
Peptides in the Heart
Recently, VIP-, neurotensin-, and Substance P-containing nerves have been localized in cardiac structures,53 including the sinoatrial node,54 specialized
conducting tissue, atrial and ventricular myocardium,
and the walls of coronary vessels (figs. 3 and 4). Both
TABLE 2. Coexistence of Peptides and Amines in Neurons of the
Central and Peripheral Nervous Systems.
Peptide
Amine
Site
Enkephalins
E, NE
Adrenal medulla,
sympathetic ganglia
Enkephalins
Dopamine
Carotid body
Somatostatin
NE
Sympathetic ganglia
VIP
Ach
Nerves to exocrine
glands and cerebral
vessels
Substance P
Serotonin
CNS nuclei
CCK
Dopamine
CNS nuclei
Ach = acetylcholine; E = epinephrine; NE = norepinephrine;
VIP = vasoactive-intestinal peptide; CCK = cholecystokininpancreozymin.
VASOACTIVE PEPTIDES/SaiVf
1-21
On the other hand, VIP relaxes isolated strips of cat
pulmonary artery in which the tone has been increased
with prostaglandin endoperoxide analog.60 In this action, VIP is at least as potent as prostacyclin, on a
molar basis.60 VIP also reduces pulmonary vascular
resistance and pulmonary arterial pressure in cats receiving infusions of prostaglandin endoperoxide
analog.61
None of the pulmonary peptides, administered
alone, has been shown to increase pulmonary microvascular permeability. However, combinations of bradykinin with hypoxia63 or with PGE^,61 and activated
complement fragments (C5a) with hypoxia or with
PGE^, can result in increased permeability of lung
microvessels. 6364
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
FIGURE 2. Vasoacalive-intestinal peptide (VIP) in nerve fibers in systemic vessels. VIP-immunofluorescence is seen in the
arteriolar wall from cat submandibular gland. (Reproduced
courtesy of Prof. Frank Sundler, Lund, Sweden.) x 200.
VIP and Substance P are known to dilate coronary
vessels. VIP also has a positive inotropic action on the
myocardium,55 binds to specific membrane receptors,
and stimulates adenylate cyclase activity in the heart.56
Vasoactive Peptides and the Pulmonary
Circulation
Peptides in the Lung
The search for peptides in the lung is relatively recent. By now, however, this search has led to the
discovery and identification of almost all the "braingut" peptides in the lung.57"59 This finding is not surprising, since the lung develops from the embryonic
foregut.
The list of peptides already shown to exist in the
lung is rapidly lengthening, and now includes at least
11 (table 3). The sites of localization of these peptides
include nerve cells and nerve endings (VIP, Substance
P, and possibly bombesin), endocrine cells (calcitonin, bombesin, and enkephalins), endothelium (angiotensin II),and other undetermined sites (table 3).
Effects of Peptides on the Pulmonary Circulation
The possible influence of vasoactive peptides on the
lung and the pulmonary circulation have only begun to
be investigated. Among the peptides normally present
in lung tissue, angiotensin II, spasmogenic lung peptide, and, to a lesser extent, Substance P contract isolated segments of pulmonary artery. Bombesin also
constricts pulmonary vessels, but the activity of its
mammalian counterpart (gastrin-releasing peptide) on
pulmonary vasculature has not been tested.57"59
Physiological Role
The physiological role of vasoactive peptides remains at an early stage of investigation. As outlined
above, many of these peptides are present in nerves
that supply blood vessels and the heart, or innervate
nerve centers that influence cardiovascular function.
Further, some of these peptides have the capacity to
function as neurotransmitters or neuromodulators.'- 2
The possibility that certain peptides do indeed serve
such a role in the regulation of cardiovascular function
seems even more likely in view of the interactions
between peptides and "classical" hormonal transmitters. Examples of such interactions in the case of VIP
are: VIP stimulates the synthesis or release of prolac65 9
65 M
as well as
t i n 65-67 g r o w t h hormone, "* and LHRH,
70
71
of renin and steroids. At the same time, VIP release
is stimulated by neostigmine72 and by serotonin.73
Certain potential physiological roles of cardiovascular peptides are suggested by the data presented above
on their localization and actions. These roles include
the regulation of regional blood flow, peripheral vascular resistance, and arterial blood pressure; and the
regulation of cardiac function, including coronary
blood flow, myocardial contractility, cardiac rhythmicity, and conductivity.
TABLE 3.
Lung Peptides and their Localization
Peptide
Localization
1.
Vasoactive-intestinal
peptide
Neurons
2.
3.
4.
5.
6.
7.
Substance P
Neurons
Bombesinlike peptide
Neurons/Endocrine cells
Calcitonin
Endocrine cells
Enkephalins
Endocrine cells
Angiotensin II
Endothelium
Eosinophil-chemo tactic
peplides
Mast cells
8.
Bradykinin
Lung tissue and blood
9.
Complement fragments
Lung tissue and blood
10.
Cholecystokinin
Undetermined
11.
"Spasmogenic lung
peptide"
Undetermined
1-22
1982 BLOOD PRESSURE COUNCIL
SUPP
I,
HYPERTENSION, VOL
5, No 2,
MARCH-APRIL
Nodus sinuatrialis
>'*
fibredDownloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
/'
' VIP-IR
fibres
Atrium dextrum
VIP-IR fibres
coronary artery
branch
VIP-IR fibres
\
FIGURE 3. VIP-immunoreactive (IR) nerve fibers in dog heart. Upper panel: Nerve fibers within the
sinoatrial node. (x 640). Lower panel: around the coronary artery and between myocardial cells of the right
atrium, (x 960). Peroxidase-antiperoxidase technique; courtesy of Prof. W.G. Forssmann, Heidelberg, W.
Germany, from unpublished work by E. Weihe, M. Reinecke and W.G. Forssmann.
1983
VASOACTIVE PEPTIDES/SaW
1-23
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
FIGURE 4. Substance P-like immunoreactivity in nerve fibers in guinea pig ventricle. (Reproduced courtesy of
Dr. Julia M. Polak, London, England.) x 365.
Peptides with vasoconstrictor or pressor activity include: angiotensin I and II, vasopressin, and prolactin. Those with vasodilator or vasodepressor activity
include: bradykinin, VIP, sauvagine, Substance P, enkephalins/endorphins, urotensin I, and parathyroid
hormone. Evidence for the possible physiological participation of some of these peptides in the maintenance
of normal blood pressure has recently become available. For example, a role for prolactin is suggested by
experiments in which newborn rats, 2-5 days old, received antiserum to prolactin.74 At 14 weeks, these rats
had lower blood pressure levels than did rats given
saline or normal rabbit serum. The possibility that
opioid peptides contribute to the reduction of blood
pressure during fasting is suggested by the observations that fasting lowers systolic blood pressure to a
greater extent in spontaneously hypertensive rats than
in normotensive rats, and that this lowering of blood
pressure is attenuated by naltrexone (2 mg/kg), an opiate receptor antagonist.75
Role of Vasoactive Peptides in
Cardiovascular Disease
Vasoactive peptides have considerable potential significance in the pathogenesis or pathologic physiology
of cardiovascular disease. Evidence for such significance has already been provided for several peptides.
Hypertension
Peptides that have been implicated in the pathogenesis of hypertension are angiotensin II, opioid peptides,
VIP, and arginine vasopressin.
1. The significance of the renin-angiotensin system in
the pathogenesis of hypertension is well established, and is reviewed elsewhere. 5
2. A possible relationship between enkephalins (predominantly hypotensive peptides) and hypertension is suggested by the report that enkephalin-like
immunoreactivity is lower in tissues from spontaneously hypertensive rats than in normal control
rats.76
3. Similarly, it has been found that VIP-sensitive
adenylate cyclase activity in cardiac tissue from
spontaneously hypertensive rats (10 weeks and
older) is greatly and selectively reduced, relative to
the responses to isoproterenol, glucagon, and fluoride. In the same animals, adenylate cyclase stimulation by VIP is normal in all other tissues examined (pancreatic acini, liver, and brain).77
4. Selective destruction of AI noradrenergic neurons
in the caudal ventrolateral medulla oblongata of
1-24
1982 BLOOD PRESSURE COUNCIL
rabbits produces a striking syndrome of accelerated
hypertension and "neurogenic" pulmonary edema.47 The terminals of these neurons are concentrated around the supraoptic and paraventricular
(magnocellular) nuclei, which secrete arginine vasopressin. This experimental lesion is associated
with a marked increase in plasma vasopressin concentrations, which probably accounts for the acute
hypertension; an antagonist of vasopressin largely
prevents this hypertension.47
Shock
Peptides that have been implicated in shock states
include bradykinin, opioid peptides, vasopressin, and
VIP.
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
Opioid Peptides
The following findings suggest that opioid peptides
may participate in mediating endotoxin shock and other forms of shock.
1. An opiate receptor antagonist, naloxone reduces
the morbidity and mortality of systemic shock from
a variety of causes, including endotoxemia, hemorrhage, anesthesia, spinal cord injury, and acid aspiration.78"83
2. Studies show that endotoxin evokes opioid peptide
secretion into the blood and cerebrospinal fluid in
sheep.84
Vasopressin
The pressor effect of circulating vasopressin may be
essential for the recovery of blood pressure following
hemorrhagic shock:
1. Hemodynamic recovery from hemorrhagic shock is
subnormal in Brattleboro rats (which have a genetic
hypothalamic lesion causing total inability to synthesize vasopressin and, as a consequence, have
diabetes insipidus).38
2. An antipressor vasopressin analog impairs recovery of blood pressure levels in normal rats bled to
hypotensive levels.3*
Vasoactive Intestinal Peptide (VIP)
It has been shown that VIP is released into the circulation during hemorrhagic and endotoxin shock in
dogs.83 The released peptide may serve to promote
blood flow to vital organs, including the heart, brain,
and splanchnic bed.
References
1. Snyder SH: Brain peptides as neurotransmitters. Science 209:
976, 1980
2. Krieger DT, Martin JB: Brain peptides. N Engl J Med 304:
876, 994, 1981
3. Jerzy Glass GB: Gastrointestinal Hormones. A volume in the
Comprehensive Endocrinology series, edited by Martini L.
New York: Raven Press, 1980
SUPP
I,
HYPERTENSION, VOL
5, No 2,
MARCH-APRIL
1983
4. Said SI: Peptides common to the nervous system and the gastrointestinal tract. In Frontiers in Neuroendocrinology, vol 6,
edited by Martini L, Ganong WF. New York: Raven Press,
1980, pp 293-331
5. Peach MJ: Renin-angiotensis system: Biochemistry and
mechanisms of action. Physiol Rev 57: 313, 1977
6. Erdos EG: Bradykinin, kallidin and kallikrein. In Handbook of
Experimental Pharmacology, edited by Erdos EG. New York:
Springer-Verlag, 1979, pp 1-817
7. Erdos EG: The angiotensin I converting enzyme. Fed Proc 36:
1760, 1977
8. Ganong WF: The renin-angiotensin system and the central
nervous system. Fed Proc 36: 1771, 1977
9. Ramsay DJ: The brain renin-angiotensin system: A re-evaluation. Neuroscience 4: 313, 1979
10. Cushman DW, Cheung HS, Sabo EF, Rubin B, Ondetti MA:
Development of specific inhibitors of angiotensin I converting
enzyme (kininase II).Fed Proc 38: 2778, 1979
11. Sweet CS, Ulm EH, Gross DM, Vassil TC, Stone CA: A new
class of angiotensin-converting enzyme inhibitors. Nature
288: 280, 1980
12. Melchiorri P: Bombesin and bombesin-like peptides of amphibian skin. In Gut Hormones, 1st ed, edited by Bloom SR.
New York: Churchill Livingstone, 1978, pp 534-540
13. McDonald TJ, Jdrnvall H, Nilsson G, Vagne M, Ghatei M,
Bloom SR, Mutt V: Characterization of a gastrin releasing
peptide from porcine non-antral gastric tissue. Biochem
Biophys Res Commun 90: 227, 1979
14. Moody TW, Pert CB, Gazdar AF, Carney DN, Minna JD:
High levels of intracellular bombesin characterize human
small-cell lung carcinoma. Science 214: 1246, 1981
15. Erisman MD, Linnoila RI, Hernandez O, DiAugustine RP,
Lazarus LH: Human lung small-cell carcinoma contains bombesin. Proc Natl Acad Sci USA 79: 1379, 1982
16. Thulin L, Olsson P: Effects of pure natural cholecystokinin on
splanchnic circulation in the dog. Acta Chir Scand 4: 1, 1973
17. Thulin L: Effects of the C-terminal octapeptide of cholecystokinin on splanchnic circulation in the dog. Acta Chir Scand 5:
1, 1973
18. Bissette G, Manberg P, Nemeroff CB, Prange AJ Jr: Neurotensin, a biologically active peptide. Life Sci 23: 2173, 1978
19. Zelis R, Mansour EJ, Capone RJ, Maso DT, Kleckner R: The
cardiovascular effects of morphine: The peripheral capacitance
and resistance vessels in human subjects. J Clin Invest 54:
1247, 1974
20. Wei ET, Lee A, Chang JK: Cardiovascular effects of peptides
related to the enkephalins and /9-casomorphin. Life Sci 26:
1517, 1980
21. Laubie M, Schmitt H, Vincent M, Remond G: Central cardiovascular effects of morphinomimetic peptides in dogs. Eur J
Pharmacol 46: 67, 1977
22. Bolme P, Fuxe K, Agnati LF, Bradley R, Smythies J: Cardiovascular effects of morphine and opioid peptides following
intracisternal administration in chloralose-anesthetized rats.
Eur J Pharmacol 48: 319, 1978
23. Sturmer E: Bioassay procedures for neurohypophysial hormones and similar polypeptides. In Handbook of Experimental
Pharmacology, edited by Eichler O, Farah A, Herken H,
Welch AD. New York: Spring-Verlag, 1968, pp 130-189
24. Pang PKT, Tenner TE Jr, Yee JA, Yang M, Janssen HF:
Hypotensive action of parathyroid hormone preparations on
rats and dogs. Proc Natl Acad Sci USA 77: 675, 1980
25. Pang PKT, Yang MCM, Kenny AD, Tenner TE, Jn Structure
and vascular activity relationship of parathyroid hormone and
some hypotensive peptides. Clin Exp Hypertens A4: 189, 1982
26. Horrobin DF, Manku MS, Burstyn PG: Effect of intravenous
prolactin infusion on arterial blood pressure in rabbits. Cardiovasc Res 7: 585, 1973
27. Mills DE, Buckman MT, Peake GT: Effects of prolactin administration and suppression on blood pressure and body fluid
compartments in the rat. Endocrinology 109: 1590, 1981
28. Montecucchi PC.Henschen A, Erspamer V: Structure of sauvagine, a vasoactive peptide from the skin of a frog. In Structure and Activity of Natural Peptides, edited by Voelter W,
VASOACTIVE PEPTlDES/SaW
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
Weitzel G. New York: Walter de Grayter, 1981, pp 225-236
29. Erspamer V, Melchiorri P, Broccardo M, Falconieri G, Falaschi P, Improta G, Negri L, Renda T: The brain-gut-skin triangle: New peptides. In Peptides, edited by Walsh JH, vol 2,
suppl 2. Fayetteville, New York: Ankho International Inc,
1981, pp7O16
30. Tyden G, Smnegard H, Thulin L, Muhrbeck O, Efendic S:
Circulatory effects of somatostatin in anesthetized man. Acta
ChirScand 145: 443, 1979
31. Leeman SE, Mroz, Carraway RE: Minireview: Substance P.
Life Sci IS: 2033, 1974
32. Holaday JW, D'Amato RJ, Faden AI: Thyrotropin-releasing
hormone improves cardiovascular function in experimental endotoxic and hemorrhagic shock. Science 213: 216, 1981
33. MacCannell K, Giraud G, Lederis K, Groves G: Use of a
specific mesenteric vasodilator peptide, urotensin I, to reduce
afterload in the dog. Can J Physiol Pharmacol 58: 1412, 1980
34. Lederis K, Letter A, McMaster D, Moore M: Complete amino
acid sequence of urotensin I, a hypotensive and corticotropinreleasing neuropeptide from catostomus. Science 218: 162,
1982
35. Said SI: Vasoactive Intestinal Peptide, edited by Said SI. New
York: Raven Press, 1982
36. Said SI: Vasodilator action of VIP: Introduction and general
considerations. In Vasoactive Intestinal Peptide, edited by
Said SI. New York: Raven Press, 1982, pp 145-148
37. Wei EP, Kontos JA, Said SI: Mechanism of vasodilator action
of vasoactive intestinal polypeptide on cerebral arterioles. Am
J Physiol 239: H765, 1980
38. Zerbe RL, Bayprh MA, Feuerstein G: Vasopressin: An essential pressor factor for blood pressure recovery following hemorrhage. Peptides 3: 509, 1982
39. Manning M, Lowbridge J, Haldar J^ Sawyer WH: Design of
neurohypophyseal peptides that exhibit selective agonistic and
antagonistic properties. Fed Proc 36: 1848, 1977
40. Hokfelt T, Johansson O, Ljungdahl A, Lungberg JM, Schultzbert M: Peptidergic neurones. Nature 284: 515, 1980
41. Burnstock G: Purinergic transmission. In Handbook of Psychopharmacology Synaptic Modulators, vol 5, edited by Iversen LL, Iversen SD. New York: Plenum, 1975, pp 131-194
42. Richardson J, Beland J: Nonadrenergic inhibitory nervous system in human airways. J Appl Physiol 41: 764, 1976
43. Burnstock G: Cholinergic and purinergic regulation of blood
vessels. In Handbook of Physiology, vol II, Vascular Smooth
Muscle, edited by Bohr DF, Somlyo AP, Sparks HV. Bethesda, Maryland: American Physiological Society, 1980, pp 567612
44. Matsuzaki Y, Hamasaki Y, Said SI: Vasoactive intestinal peptide: A possible transmitter of non-adrenergic relaxation of
guinea pig airways. Science 210: 1252, 1980
45. Hamasaki Y, Said SI: Evidence for a nonadrenergic, noncholinergic inhibitory nervous system in cat pulmonary artery
(abstr). Clin Res 29: 55OA, 1981
46. Fuxe K, Andersson K, Locatelli V, Mutt V, Lundberg J,
Hokfelt T, Agnati LF, Eneroth P, Bolme P: Neuropeptides and
central catecholamine systems: Interactions in neuroendocrine
and central cardiovascular regulation. In Neural Peptides and
Neuronal Communications, edited by Costa E, Trabucchi M.
New York: Raven Press, 1980, pp 37-50
47. Blessing WW, Sved AF, Reis DJ: Destruction of noradrenergic neurons in rabbit brainstem elevates plasma vasopressin,
causing hypertension. Science 217: 661, 1982
48. HSkfelt T, Lundberg JM, Schultzberg M, Johansson O, Ljungdahl A, Rehfeld R: Coexistence of peptides and putative transmitters in neurons. In Neural Peptides and Neuronal Communications, edited by Costa E, Trabucchi M. New York: Raven
Press, 1980, pp 1-24
49. Hokfelt T, Schultzberg M, Lundberg JM, Fuxe K, Mutt V,
Fahrenkrug J, Said SI: Distribution of vasoactive intestinal
polypeptide in the central and peripheral nervous.systems as
revealed by immunocytochemistry. In Vasoactive Intestinal
Peptide: Advances in Peptide Hormone Research Series, edited by Said SI. New York: Raven Preess, 1982, pp 65-90
50. Polak JM, Bloom SR: Distribution and tissue localization of
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71
1-25
VIP in the central nervous system and in seven peripheral
organs. In Vasoactive Intestinal Peptide: Advances in Peptide
Hormone Research Series, edited by Said SI. New York: Raven Press, 1982, pp 107-120
Hakanson R, Sundler F, Uddman R: Distribution and topography of peripheral VIP nerve fibers: Functional implications. In
Vasoactive Intestinal Peptide: Advances in Peptide Hormone
Research Series, edited by Said SI. New York: Raven Press,
1982, pp 121-144
Uddman R, Alumets J, Edvinsson L, Hikarison R, Sundler F:
VIP nerve fibres around peripheral blood vessels. Acta Physiol
Scand 112: 65, 1981
Wharton J, Polak JM, McGregor GP, Bishop AE, Bloom SR:
The distribution of substance P-like immunoreactive nerves in
the guinea-pig heart. Neuroscience 6: 2193, 1981
Weihe E, Reinecke M: Peptidergic innervation of the mammalian sinus nodes: Vasoactive intestinal polypeptide, neurotensin, Substance P. Neurosci Lett 26: 283, 1981
Said SI, Bosher LP, Spath JA, Kontos HA: Positive inotropic
action of newly isolated vasoactive intestinal polypeptide
(VIP). Clin Res 20: 29, 1972
Chatelain P, Robberecht P, De Neef P, Deschodt-Lanckman
M, Konig W, Christophe J: Secretin and VIP-stimulated adenylate cyclase from rat heart I. General properties and structural
requirements for enzyme activation. Pflugers Arch 389: 21,
1980
Said SI: Vasoactive peptides and the pulmonary circulation.
Ann NY Acad Sci 384: 207, 1982
Said SI: Pulmonary metabolism of prostaglandins and vasoactjve peptides. Ann Rev Physiol 44: 257, 1982
Said SI: Peptide hormones and neurotransmitters of the lung.
In The Endocrine Lung in Health Disease, edited by Becker
KL, Gazdar A. Philadelphia: W.B. Saunders. In press
Hamasaki Y, Said SI: Vasodilator effects of vasoactive intestinal peptide and prostacyclin on isolated cat pulmonary artery.
Am Rev Respir Dis 122: 239, 1981
Mojarad M, Said SI: Vasoactive intestinal peptide dilates pulmonary vessels in anesthetized cats. Am Rev Respir Dis 122:
239, 1981
O'Brodovich HM, Stalcup SA, Pang LM, Lipset JS, Mellins
RB: Bradykinin production and increased pulmonary endothelial permeability during acute respiratory failure in unanesthetized sheep. J Clin Invest 67: 514, 1981
Wedmore CV, Williams TJ: Control of vascular permeability
by polymorphonuclear leukocytes in inflammation. Nature
289: 646, 1981
Larsen GL: Participation of intravascular complement components in pulmonary leukocyte sequestration. Paper presented at
the Annual Meeting, American Thoracic Society, Detroit,
Michigan, May 10-13, 1981
Vijayan E, Samson WK, Said SI, McCann SM: Vasoactive
intestinal peptide: Evidence for a hypothalamic site of action to
release growth hormone, luteinizing hormone, and prolactin in
conscious ovariectomized rats. Endocrinology 104: 53, 1979
Enjalbert A, Arancibia S, Ruberg M, Priam M, Bluet-Pajot
MT, Rotsztein WH, Kordon C: Stimulation of in vitro prolactin release by vasoactive intestinal peptide. Neuroendocrinology 31: 200, 1980
Frawley LS, Neill JD: Stimulation of prolactin secretion in
rhesus monkeys by vasoactive intestinal polypeptide. Neuroendocrinology 33: 79, 1981
Chihara K, Iwaski J, Minamitani N, Kaji H, Matsukura S,
Tamaki N, MatsumotoS, FujitaT: Effect of vasoactive intestinal polypeptide on growth hormone secretion in perfused acromegalic pituitary adenoma tissues. J Clin Endocrinol Metab
54: 773, 1982
Samson WK, Burton KP, Reeves JP, McCann SM: Vasoactive
intestinal peptide stimulates luteinizing hormone-releasing
hormone release from median eminence synaptosomes. Regul
Pept 2: 253, 1982
Porter JP, Reid IA, Said SI, Ganong WF: Stimulation of renin
secretion by vasoactive intestinal peptide. Am J Physiol 234:
F306, 1982
Kowal J: VIP effects on adrenocortical cell functions: In Va-
1-26
72.
73.
74.
75.
76.
77.
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
78.
1982 BLOOD PRESSURE COUNCIL
soactive Intestinal Peptide, edited by Said SI. New York: Raven Press, 1982, pp 277-284
Bitar KN, Said SI, Weir GC, Saffouri B, Makhlouf GM: Neural release of vasoactive intestinal peptide from the gut. Gastroenterology 79: 1288, 1980
Shimatsu A, Kato Y, Matsushita N, Katakami H, Yanaihara
N, Imura H: Stimulation by serotonin of vasoactive intestinal
poly peptide release into rat hypophysical portal blood. Endocrinology 3: 338, 1982
Mills DE, Buckman MT, Peake GT: Neonatal treatment with
antiserum to prolactin lowers blood pressure in rats. Science
217: 162, 1982
Einhorn D, Young JB, Landsberg L: Hypotensive effect of
fasting: Possible involvement of sympathetic nervous system
and endogenous opiates. Science 217: 727, 1982
Di Giulio AM: Yang H-Y T, Fratta W, Costa E: Decreased
content of immunoreactive enkephalin-like peptide in peripheral tissues of spontaneously hypertensive rats. Nature 278:
646, 1979
Chatelain P, Robberecht P, De Neef P, Camus JC, Heuse D,
Christophe J: Secretin and VIP-stimulated adenylate cyclase
from rat heart II. Impairment in spontaneous hypertension.
Pflugers Arch 389: 29, 1980
Reynolds GD, Gurll NJ, Vargish T, Lechner RB, Faden AI,
SUPP
I,
79.
80.
81.
82.
83.
84.
85.
HYPERTENSION, VOL
5, No 2,
MARCH-APRIL
1983
Holaday JW: Blockade of opiate survival and cardiac performance in canine endotoxic shock. Circ Shock 7: 39, 1980
Janssen HF, Lutherer JO: Ventriculocisternal administration of
Naloxone protects against severe hypotension during endotoxin shock. Brain Res 194: 608, 1980
Faden AI, Holaday JW: Experimental endotoxin shock: The
pathophysiologic function of endorphins and treatment with
opiate antagonists. J Infect Dis 142: 229, 1980
Peters WP, Johnson MW, Friedman PA, Mitch WE: Pressor
effect of naloxone in septic shock. Lancet 1: 529, 1980
Bone RC, Jacobs ER, Potter DM, Hiller FC, Wilson FJ Jr:
Endorphins in endotoxin shock. Microcirculation 1: 285, 1981
Gahhos FN, Chiu RCJ, Hinchey EJ, Richards GK: Endorphins
in septic shock: Hemodynamic and endocrine effects of an
opiate receptor antagonist and agonist. Arch Surg 117: 1053,
1982
Carr DB, Bergland R, Hamilton A, Blume H, Kasting N,
Arnold M, Martin JB, Rosenblatt M: Endotoxin-stimulated
opioid peptide secretion: Two secretory pools and feedback
control in vivo. Science 217: 845, 1982
Bone R, Said SI, Hiller C, Wilson F: Vasoactive intestinal
polypeptide in endotoxin shock. Presented at the Annual Meeting of the American Thoracic Society in Washington, D.C.,
May 18-21, 1980. Am Rev Respir Dis 121: 113, 1980
Vasoactive peptides. State-of-the-art review.
S I Said
Hypertension. 1983;5:I17
doi: 10.1161/01.HYP.5.2_Pt_2.I17
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1983 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://hyper.ahajournals.org/content/5/2_Pt_2/I17
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in
Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located, click
Request Permissions in the middle column of the Web page under Services. Further information about this
process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Hypertension is online at:
http://hyper.ahajournals.org//subscriptions/