vasoactive peptides -...

Vasoactive PeptidesState-of-the-Art Review

SAMI I. SAID, M.D.

SUMMARY At least 16 naturally occurring peptides either constrict or dilate blood vessels. Many ofthese peptides are present in nerve cells and nerve terminals supplying systemic and pulmonary bloodvessels and the heart. Such neuropeptides are released locally as neurotransmitters, and can influencevascular tone, local and regional blood flow, arterial blood pressure, and cardiac function. There isevidence for the participation of at least some vasoactive peptides in the regulation of these functionsand in the mediation or modulation of systemic shock and arterial hypertension. The investigation ofvasoactive peptides in relation to cardiovascular function and dysfunction is at a promising threshold.(Hypertension 5 (supp I): M7-I-26, 1983)

KEY WORDS • vasopressor • vasodepressorvasodilation • shock • hypertension

hypotension * vasoconstriction

Alarge number of biologically active peptideshave been isolated and characterized in recentyears. There is a growing conviction that

these peptides participate in the regulation of manyorgan functions. Neuroscientists, endocrinologists,and gastroenterologists have led other groups in recog-nizing the likely physiological and clinical signifi-cance of these peptides, most of which are found in thebrain and gut.1"1

Since many biologically active peptides are capableof influencing vascular smooth muscle, and thus bloodflow and blood pressure, peptides with these vasoac-tive properties are reviewed here. Emphasis is placedon the cardiovascular effects of the more recently iden-tified peptides, with special reference to their possibleroles in the regulation of blood pressure in normal andabnormal states. Bradykinin and angiotensins, whichare extensively reviewed elsewhere, are only brieflymentioned here.

Biological Activity of PeptidesWhich Peptides are Vasoactive?

Peptides with vasoactive properties are given in theaccompanying list (see box), which is not meant to becomplete. For some of these peptides (e.g., angioten-sin II, bradykinin), vasoactivity is a dominant featureof their biological actions; for others (e.g., prolactin,parathyroid hormone), the pressor or vasodepressor

From the Department of Medicine, University of OklahomaHealth Sciences Center and Veterans Administration Medical Cen-ter, Oklahoma City, Oklahoma.

Address for reprints: Sami I. Said, M.D., University of Oklaho-ma Health Sciences Center, P.O. Box 26307, Oklahoma City,Oklahoma 73126.

activity has generally been overshadowed by other ac-tions of the peptide.

As will become apparent in the following para:

graphs, the ability to induce either vasodilation or va-soconstriction is shared by a variety of apparently un-related peptides. It is possible in some instances,however, t o ' recognize certain structural featuresamong these peptides that correlate with their vasodila-tor or vasoconstrictor activity. Such features will benoted.

AngiotensinsAngiotensin II (table 1) is one of the most potent

systemic vasopressors known. Its formation from an-giotensin I through the action of angiotensin-convert-ing enzyme, the localization and properties of this en-zyme, and the physiology, pathophysiology, andpharmacology of the renin-angiotensin systems in thebody are topics of recent comprehensive reviews.5""

BombesinA 14-residue peptide (table 1) isolated from the skin

of the frog Bombina bombina, bombesin has spasmo-genic activity on a variety of vascular and non-vascularsmooth muscle structures.12 It induces vasoconstric-tion and systemic hypertension in most animal species,hypotension in monkeys, but neither in humans. Amammalian counterpart of the amphibian peptide is the27-residue gastrin-releasing peptide, which has beenfound in the brain and gastrointestinal tract.13 Bombe-sin itself may also occur in human oat-cell cancer ofthe lung.1415

BradykininA potent systemic vasodilator and vasodepressor,

bradykinin (table 1) also increases systemic, but not

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1-18 1982 BLOOD PRESSURE COUNCIL SUPP I, HYPERTENSION, VOL 5, No 2, MARCH-APRIL 1983

Vasoactive Peptides

1. Angiotensin I and II2. Bombesin3. Bradykinin4. Cholecystokinin-pancreozymin5. Neurotensin6. Opioid peptides7. Oxytbcin8. Parathyroid hormone9. Prolactin

10. Sauvagine11. Somatostatin12. Substance P13. Thyrotropin-releasing hormone14. Urotensin15. Vasoactive intestinal peptide16. Vasopressjn

pulmonary, microvascular permeability. The genera-tion, inactivation, and biological role of bradykininhave 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 inthe brain, especially the cerebral cortex, and in periph-eral nerves. In addition to stimulating gallbladder con-traction and pancreatic enzyme secretion, it has dis-tinct, though limited, vasoactive properties. Thepeptide and its C-terminal octapeptide fragment inducesplanchnic vasodilation and mild hypotension in anes-thetized dogs.16 l7 CCK is naturally present in severalmolecular forms, including 4-, 8-, 33- and 39-residuepeptides.

NeurotensinA 13-residue peptide (table 1), neurotensin is pres-

ent in the central and peripheral nervous systems and

gastrointestinal organs. It causes vasodilation, hypo-tension, peripheral cyanosis, and increased vascularpermeability in anesthetized rats. In dogs, however,neurotensin is a systemic vasoconstrictor.18 Thechemically related amphibian peptide, xenopsin, isalso vasoactive.

Opioid PeptidesThe endogenous opioid peptides, including endor-

phins and enkephalins, have important effects on car-diovascular function. The specific effects in experi-mental animals depend on the individual peptide andthe method of its administration. Like morphine,opioid peptides generally cause peripheral vasodilationand a fall in arterial blood pressure, when given intra-venously.1920 Administered intracisternally in anes-thetized dogs and rats, morphine, /3-endorphin, D-ala2-met enkephalin and D-ala2-met-enkephalinamideinduce hypotension and bradycardia, while a-endor-phin induces hypertension.21-22 Centrally adminis-tered, met-enkephalin is vasopressor in rats but inef-fective in dogs.

OxytocinOne of the two "neurohypophyseal peptides"

(though actually secreted in the hypothalamic magno-cellular nuclei), oxytocin has vasodepressor activity,at least in birds. The ability of oxytocin to lower chick-en blood pressure is the basis for a bioassay method forthis peptide.23

Parathyroid Hormone (PTH)Bovine parathyroid hormone (1-34 fragment) pro-

duces dose-related arterial hypotension in dogs, ratsand other species. This action is not mediated byadrenergic, cholinergic, or histamine receptors.24"PTH exerts a direct vasodilator action in perfused rathindlimbs and in dog renal, hepatic, pancreatic andcoronary vascular beds; it also relaxes isolated strips ofrabbit aorta.24-M The vasodilator effect of PTH in dogsis evident at doses that are too small (0.01 U/kg) tocause hypercalcemia. Chemical manipulations of the

TABLE 1. Amino-Acid Sequences of Some Vasoactive Peptides

Peptide Amino-acid sequence

Angiotensin I

Angiotensin II

Bradykinin

Substance P

Neurotensin

Somatostatin

Bombesin

Thyrotropin-releasing hormone

Oxytocin

Vasopressin

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 -Se r -Cys - 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



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VASOACTIVE PEPTlDES/Sa/rf 1-19

PTH molecule show that distinct and different parts ofthe sequence are responsible for the hypercalcemic andvasoactive properties.25 The occurrence of basic aminoacids in adjacent positions may be important to thevasodilator activity of PTH." Other vasodilator pep-tides, including VIP and neurotensin, also possess ad-jacent basic residues.

ProlactinAmong the least widely known actions of prolactin

is its ability to influence vascular smooth muscle. Inlow concentrations (0.6 /u.g/hr), acute or chronic ad-ministration of ovine prolactin raises blood pressure inrabbits and rats and potentiates pressor responses of ratmesenteric vessels to norepinephrine and angiotensinII.26-27 Infusions of higher concentrations (8.9 Aig/hr)of prolactin decrease blood pressure in rats.27

SauvagineRecently isolated from the skin of the frog Phyllo-

medusa sauvagei, sauvagine is a 40-residue peptidewith a long-lasting hypotensive activity in many spe-cies, including humans.28-N Sauvagine, structurally re-lated to corticotropin-releasing factor, also has potentendocrine effects, provoking the release of ACTH and/3-endorphin from the pituitary.28-29

SoniatostatinThis hypothalamic tetradecapeptide (table 1), which

is also present in peripheral tissues, can influence vas-cular smooth muscle. Intravenous infusion of somato-statin (1 /xg/kg) in anesthetized human subjects re-duced splanchnic blood flow (by up to 56%),augmented external iliac blood flow (by 43%), andraised mean arterial blood pressure (by 20%).w

Substance PWidely distributed in the brain and in nerves supply-

ing many organs, Substance P is an 11-residue peptidewith some structural similarities to bradykinin (table 1)and major actions on the circulation. These actionsinclude peripheral vasodilation and transient systemichypotension.31 A related peptide, physalaemin, origi-nally discovered in amphibian skin, has also beenfound 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 persistsfor 30 minutes.32 TRH (table 1) appears to antagonizethe cardiovascular effects of endogenous opiate pep-tides, which have overall vasodepressbr activity.32

Urotensin IA 41-residue peptide recently isolated from the uro-

physis of a teleost fish, Catostomus commersoni; uro-tensin I is a selective dilator of mesenteric vessels inmammals.33-34 It also induces hypotension and in-creases cardiac output in anesthetized dogs.33-M Theseeffects are not influenced by adrenergic, histaminer-gic, or muscarinic cholinergic blockade. Urotensin I

shows a striking sequence homology with ovine corti-cotropin-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 peripheralnerves of all mammalian species and lower forms.35

t he 28-residue peptide has potent vasodilator activityin coronary, splanchnic, extremity, extracranial, andother vascular beds.35 As a consequence of this gener-alized vasodilation, VIP induces systemic hypotension(fig. I).3 3-x The vascular effects of VIP are independ-ent of adrenergic or cholinergic receptors and, with theexception of the vasodilation of pial vessels,37 are notmediated by prostaglandin release. The related pep-tides, secretin and glucagon, have considerablyweaker activity on vascular and nonvascular smoothmuscle.

VasopressinThe second of the neurohypophyseal peptides, va-

sopressin has pressor activity that was the basis for itsrecognition and its given name. On a molar basis,vasopressin is as potent as angiotensin II or norepi-nephrine in raising mean arterial blood pressure ofrats.38 Arginine-vasopressin (table 1) has equal pressorand antidiuretic activities. Structural changes in themolecule (e.g., deamination at Position 1, substitutionof a more lipophilic amino acid for Gin at Position 4,and of D-for L-Arg at Position 8) have led to thesynthesis of peptides with enhanced antidiuretic, rela-tive to pressor, activity.39 Thus, l-deamino-4 valine-8-D arginine vasopressin has no detectable vasopressoractivity, but has four times the antidiuretic activity ofarginine-vasopressin. The latter compound also an-tagonizes the pressor response of arginine vasopressin.Other substitutions have resulted in enhancement ofthe pressor/antidiuretic activity. For example, 8-or-nithine vasopressin has a pressor/antidiuretic activityratio of 4, and 2-phenylalanine-8-ornithine vasotocinis the most highly selective pressor/antidiuretic agentknown to date, with a pressor/antidiuretic activity ratioof 255.w As noted earlier, the closely related peptideoxytocin is actually vasodepressor, at least in birds.23

Distribution of Vasoactive PeptidesPeptides Hormones and Neurotransmitters

Few of the vasoactive peptides (e.g., bombesln,CCK, parathyroid hormone) are localized in endocrinecells. Such peptides may function as hormones, actingon remote target organs, or as locally active paracrinesecretions. On the other hand, most other peptides arelocalized mainly in nerve cell bodies, nerve fibers andnerve endings. These peptides, occurring in neurons ofthe central and peripheral nervous systems, are knownas neuropeptides. Many are already known to exhibitcharacteristic features of neurotransmitters, such asconcentration in nerve terminals and synaptosomes,axonal transport, and release with depolarizing con-centrations of K+ in the presence of Ca2+.'



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FIGURE 1. Vasodilator and hypotensive effects of vasoactive-intestinal peptide (VIP) in anesthetized dog. Infusion of peptide (300ng/kg) into a superficial branch of a femoral artery caused a greater than fivefold increase in femoral arterial blood flow (continuoustracing), measured by an electromagnetic flow probe, and a 60 mm Hgfall in mean aortic blood pressure (interrupted tracing). Theinfusion lasted 30 seconds (bar). Blood flow was still elevated 16 minutes after the infusion. (Reproduced from Said SI: VasoactiveIntestinal Peptide. New York, Raven Press, 1982 with permission.)

Neuropeptides are. being increasingly recognized asforming a third component of the autonomic nervoussystem, the peptidergic system of nerves.m The exis-tence of a nonadrenergic, noncholinergic nervous sys-tem has been demonstrated in many tissues and organs,including blood vessels.41-43 The identity (or identities)of the transmitters) of this system, sometimes alsoknown as the "purinergic" system, has been in dis-pute.41 Certain neuropeptides, especially VIP, are nowunder investigation as the possible responsibletransmitters.44-45

The localization of vasoactive peptides in the centralnervous system is of special interest in relation to theirpossible regulatory role. For example, neurons con-taining Substance P, VIP, and enkephalins innervatecardiovascular centers in the nucleus tractus solitariusand other nuclei;46 and norepinephrine-containing neu-rons innervate the large hypothalamic neuroendocrinecells 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 hasdocumented the frequent occurrence, in the same neu-rons, of more than one transmitter.48 These are usuallya peptide together with a catecholamine, acetylcho-line, or serotonin. Examples of this coexistence (andsometimes co-release) of peptides and other neuro-transmitters are given in table 2.

Vasoactive Peptides and the Systemic CirculationPeptides in Systemic Vessels

Immunohistochemical techniques have demonstrat-ed the presence of some vasodilator peptides in nerve

fibers and nerve terminals within the walls of systemicblood vessels. This distribution is best exemplified byVIP and Substance P. VIP-containing nerves supplyvessels to the digestive organs, upper respiratory pas-sages, tracheo-bronchial tree, skin, skeletal muscle,brain, ocular and extracranial structures, genitourinarysystem, adrenal gland, and other sites49"52 (fig. 2). Lo-cally released, VIP is therefore well positioned to in-fluence blood flow to individual organs, regionalblood flow, total peripheral vascular resistance, andarterial blood pressure.

Peptides in the HeartRecently, VIP-, neurotensin-, and Substance P-con-

taining nerves have been localized in cardiac struc-tures,53 including the sinoatrial node,54 specializedconducting 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 theCentral and Peripheral Nervous Systems.

Peptide

Enkephalins

Enkephalins

Somatostatin

VIP

Substance P

CCK

Amine

E, NE

Dopamine

NEAch

Serotonin

Dopamine

Site

Adrenal medulla,sympathetic ganglia

Carotid body

Sympathetic ganglia

Nerves to exocrineglands and cerebralvessels

CNS nuclei

CNS nuclei

Ach = acetylcholine; E = epinephrine; NE = norepinephrine;VIP = vasoactive-intestinal peptide; CCK = cholecystokinin-pancreozymin.



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VASOACTIVE PEPTIDES/SaiVf 1-21

FIGURE 2. Vasoacalive-intestinal peptide (VIP) in nerve fi-bers in systemic vessels. VIP-immunofluorescence is seen in thearteriolar wall from cat submandibular gland. (Reproducedcourtesy of Prof. Frank Sundler, Lund, Sweden.) x 200.

VIP and Substance P are known to dilate coronaryvessels. VIP also has a positive inotropic action on themyocardium,55 binds to specific membrane receptors,and stimulates adenylate cyclase activity in the heart.56

Vasoactive Peptides and the PulmonaryCirculation

Peptides in the LungThe search for peptides in the lung is relatively re-

cent. By now, however, this search has led to thediscovery and identification of almost all the "brain-gut" peptides in the lung.57"59 This finding is not sur-prising, since the lung develops from the embryonicforegut.

The list of peptides already shown to exist in thelung is rapidly lengthening, and now includes at least11 (table 3). The sites of localization of these peptidesinclude nerve cells and nerve endings (VIP, SubstanceP, and possibly bombesin), endocrine cells (calci-tonin, bombesin, and enkephalins), endothelium (an-giotensin II),and other undetermined sites (table 3).

Effects of Peptides on the Pulmonary CirculationThe possible influence of vasoactive peptides on the

lung and the pulmonary circulation have only begun tobe investigated. Among the peptides normally presentin lung tissue, angiotensin II, spasmogenic lung pep-tide, and, to a lesser extent, Substance P contract iso-lated segments of pulmonary artery. Bombesin alsoconstricts pulmonary vessels, but the activity of itsmammalian counterpart (gastrin-releasing peptide) onpulmonary vasculature has not been tested.57"59

On the other hand, VIP relaxes isolated strips of catpulmonary artery in which the tone has been increasedwith prostaglandin endoperoxide analog.60 In this ac-tion, VIP is at least as potent as prostacyclin, on amolar basis.60 VIP also reduces pulmonary vascularresistance and pulmonary arterial pressure in cats re-ceiving infusions of prostaglandin endoperoxideanalog.61

None of the pulmonary peptides, administeredalone, has been shown to increase pulmonary micro-vascular permeability. However, combinations of bra-dykinin with hypoxia63 or with PGE^,61 and activatedcomplement fragments (C5a) with hypoxia or withPGE^, can result in increased permeability of lungmicrovessels.6364

Physiological RoleThe physiological role of vasoactive peptides re-

mains at an early stage of investigation. As outlinedabove, many of these peptides are present in nervesthat supply blood vessels and the heart, or innervatenerve centers that influence cardiovascular function.Further, some of these peptides have the capacity tofunction as neurotransmitters or neuromodulators.'-2

The possibility that certain peptides do indeed servesuch a role in the regulation of cardiovascular functionseems even more likely in view of the interactionsbetween peptides and "classical" hormonal transmit-ters. Examples of such interactions in the case of VIPare: VIP stimulates the synthesis or release of prolac-t i n 65-67 g r o w t h hormone,65"*9 and LHRH,65 M as well asof renin70 and steroids.71 At the same time, VIP releaseis stimulated by neostigmine72 and by serotonin.73

Certain potential physiological roles of cardiovascu-lar peptides are suggested by the data presented aboveon their localization and actions. These roles includethe regulation of regional blood flow, peripheral vas-cular resistance, and arterial blood pressure; and theregulation of cardiac function, including coronaryblood flow, myocardial contractility, cardiac rhyth-micity, and conductivity.

TABLE 3. Lung Peptides and

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

Peptide

Vasoactive-intestinalpeptide

Substance P

Bombesinlike peptide

Calcitonin

Enkephalins

Angiotensin II

Eosinophil-chemo tacticpeplides

Bradykinin

Complement fragments

Cholecystokinin

"Spasmogenic lungpeptide"

their Localization

Localization

Neurons

Neurons

Neurons/Endocrine cells

Endocrine cells

Endocrine cells

Endothelium

Mast cells

Lung tissue and blood

Lung tissue and blood

Undetermined

Undetermined



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Nodus sinuatrialis

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Atrium dextrum

fibred-

/ '' VIP-IR

fibres

VIP-IR fibres

coronary arterybranch

VIP-IR fibres

\

FIGURE 3. VIP-immunoreactive (IR) nerve fibers in dog heart. Upper panel: Nerve fibers within thesinoatrial node. (x 640). Lower panel: around the coronary artery and between myocardial cells of the rightatrium, (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.



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VASOACTIVE PEPTIDES/SaW 1-23

FIGURE 4. Substance P-like immunoreactivity in nerve fibers in guinea pig ventricle. (Reproduced courtesy ofDr. Julia M. Polak, London, England.) x 365.

Peptides with vasoconstrictor or pressor activity in-clude: angiotensin I and II, vasopressin, and prolac-tin. Those with vasodilator or vasodepressor activityinclude: bradykinin, VIP, sauvagine, Substance P, en-kephalins/endorphins, urotensin I, and parathyroidhormone. Evidence for the possible physiological par-ticipation of some of these peptides in the maintenanceof normal blood pressure has recently become avail-able. For example, a role for prolactin is suggested byexperiments in which newborn rats, 2-5 days old, re-ceived antiserum to prolactin.74 At 14 weeks, these ratshad lower blood pressure levels than did rats givensaline or normal rabbit serum. The possibility thatopioid peptides contribute to the reduction of bloodpressure during fasting is suggested by the observa-tions that fasting lowers systolic blood pressure to agreater extent in spontaneously hypertensive rats thanin normotensive rats, and that this lowering of bloodpressure is attenuated by naltrexone (2 mg/kg), an opi-ate receptor antagonist.75

Role of Vasoactive Peptides inCardiovascular Disease

Vasoactive peptides have considerable potential sig-nificance in the pathogenesis or pathologic physiology

of cardiovascular disease. Evidence for such signifi-cance has already been provided for several peptides.

HypertensionPeptides that have been implicated in the pathogene-

sis of hypertension are angiotensin II, opioid peptides,VIP, and arginine vasopressin.

1. The significance of the renin-angiotensin system inthe pathogenesis of hypertension is well estab-lished, and is reviewed elsewhere.5

2. A possible relationship between enkephalins (pre-dominantly hypotensive peptides) and hyperten-sion is suggested by the report that enkephalin-likeimmunoreactivity is lower in tissues from sponta-neously hypertensive rats than in normal controlrats.76

3. Similarly, it has been found that VIP-sensitiveadenylate cyclase activity in cardiac tissue fromspontaneously hypertensive rats (10 weeks andolder) is greatly and selectively reduced, relative tothe responses to isoproterenol, glucagon, and flu-oride. In the same animals, adenylate cyclase stim-ulation by VIP is normal in all other tissues exam-ined (pancreatic acini, liver, and brain).77

4. Selective destruction of AI noradrenergic neuronsin the caudal ventrolateral medulla oblongata of



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rabbits produces a striking syndrome of acceleratedhypertension and "neurogenic" pulmonary ede-ma.47 The terminals of these neurons are concen-trated around the supraoptic and paraventricular(magnocellular) nuclei, which secrete arginine va-sopressin. This experimental lesion is associatedwith a marked increase in plasma vasopressin con-centrations, which probably accounts for the acutehypertension; an antagonist of vasopressin largelyprevents this hypertension.47

Shock

Peptides that have been implicated in shock statesinclude bradykinin, opioid peptides, vasopressin, andVIP.

Opioid PeptidesThe following findings suggest that opioid peptides

may participate in mediating endotoxin shock and oth-er forms of shock.1. An opiate receptor antagonist, naloxone reduces

the morbidity and mortality of systemic shock froma variety of causes, including endotoxemia, hemor-rhage, anesthesia, spinal cord injury, and acid aspi-ration.78"83

2. Studies show that endotoxin evokes opioid peptidesecretion into the blood and cerebrospinal fluid insheep.84

VasopressinThe pressor effect of circulating vasopressin may be

essential for the recovery of blood pressure followinghemorrhagic shock:1. Hemodynamic recovery from hemorrhagic shock is

subnormal in Brattleboro rats (which have a genetichypothalamic lesion causing total inability to syn-thesize vasopressin and, as a consequence, havediabetes insipidus).38

2. An antipressor vasopressin analog impairs recov-ery of blood pressure levels in normal rats bled tohypotensive levels.3*

Vasoactive Intestinal Peptide (VIP)It has been shown that VIP is released into the circu-

lation during hemorrhagic and endotoxin shock indogs.83 The released peptide may serve to promoteblood flow to vital organs, including the heart, brain,and splanchnic bed.

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