Vasopressin
arginine vasopressin (AVP)
antidiuretic hormone (ADH)
Chemistry:
Nonapeptide which differs from oxytocin by only 2
amino acids
Clinical preparations:
synthetic arginine vasopressin (human form)
desmopressin (1-deamino-8-D-arginine vasopressin,
DDAVP), synthetic analog with longer duration of
action and selective activity for renal effects
Vasopressin secretion
•Stimulated by:
• Increasing extracellular fluid osmolality
• Falling blood pressure
• Decreased extracellular fluid volume without change
in osmolality (as in hemorrhage)
• The renin-angiotensin II system
Vasopressin secretion
•Other stimulatory factors:
•acetylcholine
•histamine
•dopamine
•glutamine
cholecystokinin
prostaglandins
neuropeptide Y
substance P
VIP
•Inhibitory factors:
•stress:
• pain
• hypoxia
nausea
•
atrial natriuretic factor (ANF)
GABA
opioid peptides
AVP secretion: Pharmacological agents
Stimulators:
Inhibitors:
nicotine
epinephrine
vincristine (antimitotic)
cyclophosphamide
(antineoplastic agent)
morphine (at high doses)
ethanol
glucocorticoids
phenytoin
tricyclic antidepressants
imipramine
lithium
Stimulates secretion but
inhibits renal response
morphine (at low doses)
butorphanol, oxilorphan (K
agonists)
antipsychotics
tricyclic phenothiazines
chlorpromazine
butyrophenones
haloperidol
AVP: Mechanism of action
• Three specific G-protein -coupled receptors:
V1a binding
 +
phospholipase C
 +
IP3, Ca2+
 +
contraction of
vascular and GI
smooth muscle
V1b binding
 +
phospholipase C
 +
IP3, Ca2+
 +
potentiation of
ACTH secretion
by anterior
pituitary
V2 binding
+
adenylate cyclase
+
cAMP
+
insertion of
aquaporin into
luminal membrane of
renal medullary
collecting ducts
AVP Actions
• V2-mediated effects: Water retention
– occur at much lower concentrations than those
mediated by V1
• V1 pressor effects: Vasoconstriction
– may be most important in maintainting arterial
pressure in the face of extreme hypovolemia and
hypotension
Vasopressin: Clinical uses
• Treatment of central Diabetes Insipidus (DI)
– DI: reduced water reabsorption and polyuria
• Causes of DI:
•
AVP deficiency
•
Central = neurogenic = pituitary D.I.
•
May be congenital or acquired
•
Impaired renal response to AVP
•
nephrogenic D.I.
Vasopressin: Clinical uses
G.I. Applications
 Based on V1-mediated contraction of GI smooth
muscle: for post-operative ileus and to dispel intestinal
gas before abdominal imaging
 Based on V1-mediated contraction of vascular smooth
muscle: for emergency treatment of bleeding
esophageal varices (varicose veins) and for acute
hemorrhagic gastritis
Vasopressin: Clinical uses
• Diagnostic: To differentiate central and
nephrogenic D.I.
Vasopressin: Adverse effects
•
•
•
•
Primarily a result of unwanted V1 effects:
constriction of blood vessels (coronary vessels” angina)
stimulation of GI muscle contraction (colic)
Cross-reaction with the oxytocin receptor (stimulation
of uterine muscle)
The Neuropeptide
Substance P
Substance P distribution
CNS
• Particularly high:• Striatum
• Substantia nigra
• Hypothalamus
• Dorsal horn of spinal cord
• C and Ad fibres
Periphery
• Ileum
• Colon
• Heart
• Urinary bladder
(smooth muscle contraction)
• blood vessel walls (relaxation vascular smooth muscle)
P is for neuroPeptide
•
• Belongs to peptide family Tachykinins (Tachykinin = fast contraction
of smooth muscle).
• 3 mammalian peptides.
Sequences
Substance P
Neurokinin A
(Subtance K)
Neurokinin B
(Neuromedin K)
Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2
His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH2
Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH2
Phe-X-Gly-Leu-Met-NH2
N-Terminal - High affinity and selectivity
• Widely distributed within CNS and Periphery
• Smooth muscle contraction
• Vascular relaxation
• Dorsal roots of spinal cord
C-Terminal - Low affinity general binding and
activation of receptor
Receptors
3 mammalian Neurokinin receptors.
• G-Protein coupled receptors (GPCR’s),
• Receptor Relative affinity
•
•
• NK1
Substance P > Neurokinin A > Neurokinin B
• NK2
Neurokinin A > Neurokinin B > Substance P
• NK3
Neurokinin B > Neurokinin A > Substance P
•However all 3 Neurokinins:
• high affinity
act as full agonists on the 3 receptor subtypes =
poor selectivity.
• Relative order of potency of neurokinins is still used in
neurokinin receptor classification.
Inactivation of Substance P
• SP
is hydrolysed by peptidases.
• Inactivated
• Converted to product with different biological function
Peptidases that inactivate substance P.
Substance Pendopeptidase
Arg-Pro-Lys-Pro-Gln-Gln-Phe - Phe-Gly-Leu-Met-NH2
Angiotensinconverting enzyme
Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe - Gly-Leu-Met-NH2
Neutral
NH2
endopeptidase
Arg-Pro-Lys-Pro-Gln-Gln - Phe-Phe-Gly - Leu-Met-
• SP endopeptidase specific for SP
P is for Pain!
•Present in:
• Dorsal root = afferent (sensory)
• Ventral = efferent (motor)
• Nociception = mechanism whereby noxious peripheral
stimuli are transmitted to the CNS.
Detection by primary afferent neurons.
Unmyelinated C-fibres convey delayed pain to dorsal horn
of spinal cord.
Released SP excites dorsal horn neurons. Neuronal
transmission to thalamus.
SP released form primary C-afferent terminals produces
slow EPSP
Substance P and NK1 as therapeutic targets
Huntington’s disease, substantia nigra
Parkinson’s disease, globus pallidus =
Reduction in SP
Alzheimer’s disease, cerebral cortex
Arthritis = Results in increased release of SP in
Dorsal horns.
Increased SP in synovial fluid.
Headaches = SP has a dilator effect on human
cerebral vessels = inflammation.
Anxiety and depression = NK1 antagonist alleviates
stress induced symptoms.
Effective antidepressant in human clinical trials.
C
CP-96345 : is non-peptide, potent and selective NK1 antagonist.
Exhibited anti-nociceptive activity.
Current development of new NK1 and NK2
antagonists.
Bradykinin (BK)
• Bradykinin is a nonapeptide.
• It is clipped out of kininogen by a
proteolytic enzyme, kallikrein.
• It is converted by kininase I to an
octapeptide, BK1-8(des-Arg-BK), which is
inactivated by angiotensin-converting
enzyme in the lung.
•
Bradykinin
Generation and deactivation
Bradykinin
• Pharmacological actions:
–
–
–
–
Vasodilatation (By generating NO and PGI2)
Increased vascular permeability.
Stimulation of pain nerve endings.
Stimulation of epithelial ion transport and fluid
secretion in airways and GIT.
– Contraction of intestinal and uterine smooth
muscles.
Bradykinin
• Receptors:
– B2: constitutive: Not inducible.
• Selective antagonist: Icatibant.
– B1: inducible (induced in inflammation).
• Selective antagonist: des-Arg Hoe 140)
Neuropeptide Y
• Neuropeptide Y: cotransmitter with
noradrenaline in postganglionic sympathetic
neurons (e.g. blood vessels)
= Facilitates constirctor action of
NA and inhibits NA release
Vasoactive intestinal peptide
• Cotransmitter with Ach in parasympathetic
nerves to salivary glands = vasodilatation.
• NANC innervation of airways smooth
muscle= Bronchodialtion.