Vasoactive peptides

1. Vasoactive peptides
Dr Shinde Viraj Ashok
Department of Pharmacology
Junior Resident

2. Overview
Definition
Renin angiotensin system
Kallikrein kinin system
Endothelins
Vasoactive intestinal peptide & others

3. definition
Vasoactive peptide means
peptide tending to cause
vasodilation or vasoconstriction
or influencing tone or caliber of
blood vessels

4. Renin - ANGIOTENSIN
system

5. Renin (aspartyl protease enzyme)
 Synthesized & stored - juxtaglomerular apparatus of nephron
 Control of Renin Release
Renin released - activity of renin-angiotensin system
A. Macula Densa
 ↑ NaCl delivery or concentration to macula densa - ↓ renin
release
B. Renal Baroreceptor
 ↑ renal artery pressure - ↓ renin release & vice versa

6. C. Sympathetic Nervous System
 Norepinephrine - stimulates renin release
D. Angiotensin
 Angiotensin II - inhibits renin release
E. Pharmacologic Alteration of Renin Release
 Renin release stimulated by
o Vasodilators (hydralazine, minoxidil, nitroprusside)
o ß-adrenoceptor agonists, a-adrenoceptor antagonists
o Phosphodiesterase inhibitors (eg, theophylline, milrinone,
rolipram)
o Diuretics & anaesthetics

7. ACTIONSOFANGIOTENSINII
renin-angiotensin system - regulates of fluid &
electrolyte balance & arterial blood pressure
Blood Pressure
Angiotensin II -potent pressor agent
Adrenal Cortex - stimulate aldosterone synthesis &
release
Kidney - renal vasoconstriction, ↑ proximal tubular
sodium reabsorption & inhibit release of renin

8. Cell Growth
 Mitogenic for vascular & cardiac muscle cells
(cardiovascular hypertrophy)
 Overactivity of renin angiotensin system -
development of hypertensive vascular disease
 ACE inhibitors & ANG II receptor antagonists
slow or prevent morphologic changes
(remodeling) following myocardial infarction

9. ANGIOTENSINRECEPTORS
ANG II receptors
 AT1 receptors & AT2 receptors
 G protein-coupled
 Located on plasma membrane of target cells
AT 1 Receptors AT 2 Receptors
Location – vascular smooth
muscles
Foetus – widely distributed
Adults – adrenal medulla ,
vascular endothelium & brain
Function – vasoconstriction , cell
growth in heart & arteries ,
secretion of aldosterone ,
reabsorption from PCT & DCT
Vasodilatation
Antiproliferative
Apoptosis

10. ACE
inhibitors
• Captopril,
enalapril ,
Lisinopril,
Ramipril,
Perindopril
Angiotensin
receptor
antagonist
• Losartan
,valsartan
,telmisartan ,
olmesartan
Blockers of
renin
release
• Β
adrenoceptor
blocker –
propranolol
Renin
inhibitors
• Aliskiren ,
enalkiren &
remikiren
INHIBITION OF RENIN-
ANGIOTENSIN SYSTEM

11. Angiotensin-Converting Enzyme
Inhibitors
 All ACEI prodrugs - except captopril &
lisinopril
 Enalaprilat - IV route - meant for use in
hypertensive emergencies
 ↓ systemic vascular resistance without ↑
heart rate & promote natriuresis -
effective in treatment of hypertension

12. Continued ACEI
 ↓ morbidity & mortality in heart failure & left
ventricular dysfunction after myocardial
infarction
 Delay progression of diabetic nephropathy
 Adverse effects – dry cough , rashes ,
dysguesia
 Contraindicated - in pregnancy (fetal kidney
damage) , serum creatinine > 3.5 mg/ dl

13. Angiotensin Receptor Blockers
 Antagonists of AT1 receptors
 Orally active, potent
 Efficacy - hypertension - similar to ACE
inhibitors
 Slow progression of diabetic nephropathy

14. Continued ARB
 Valsartan - ↓ incidence of diabetes in
patients with impaired glucose tolerance
 Effective in treatment of heart failure
(useful alternative - ACE inhibitors not
well tolerated)
 Lower incidence of cough & angioedema

15. Marfan syndrome (Connective tissue
disorder)
 Associated with
o Aortic disease
o ↑ transforming growth factor (TGF)-ß
signalling
 ANG II - ↑ TGF-ß levels - blockade of
renin-angiotensin system might be
beneficial in Marfan syndrome
 Losartan - Promising initial results &
clinical trials are underway

16. Renin Inhibitors
 E.g. – enalkiren & remikiren
 limited by low potency, poor bioavailability & short
duration of action
Aliskiren
o Approved for treatment of hypertension
o In healthy subjects - produces dose-dependent
reductions in plasma renin activity , ANG I , II &
aldosterone concentrations
o Safety & tolerability comparable to angiotensin
antagonists & placebo
o Contraindicated in pregnancy
o Eliminates renin rise produced by ACE inhibitors, ARBs
& diuretics - results in greater antihypertensive
effect

17. kinins

18. Formation & metabolism of kinins
The kallikrein-kinin system. Kininase II is identical to converting enzyme
peptidyl dipeptidase (ACE)
(Plasma)
( Urine )

19. PHYSIOLOGIC &
PATHOLOGIC EFFECTS OF
KININSEffects on Cardiovascular System
 Vasodilatation results from
o Direct inhibitory effect - arteriolar
smooth muscle
o Release of nitric oxide or vasodilator
prostaglandins (PGE2 & PGI2)
 Venous contraction result from
o Direct stimulation - venous smooth muscle
o Release of venoconstrictor prostaglandins
(PGF2a)

20. cont’d PHYSIOLOGIC & PATHOLOGIC EFFECTS
OF KININS
Effects on Endocrine & Exocrine
Glands
 Smooth muscle –
o May modulate tone of salivary & pancreatic ducts
o Regulate gastrointestinal motility
o Local modulators of blood flow
 Regulate transport of substances in gastrointestinal tract &
kidney
o Influencing transepithelial transport of water, electrolytes ,
glucose & amino acids
 Kallikreins : Physiologic activation of prohormones (proinsulin
& prorenin)

21. Cont’d PHYSIOLOGIC & PATHOLOGIC
EFFECTS OF KININS
Role in Inflammation & Pain
 Bradykinin produce four classic symptoms
of inflammation
o redness, local heat, swelling & pain
 Kinins - potent pain producing substances
- when applied to blister base or injected
intradermally

22. Cont’d PHYSIOLOGIC &
PATHOLOGIC EFFECTS OF
KININS
Role in Hereditary Angioedema
 Rare autosomal dominant disorder
 Deficiency or dysfunction of C1 esterase
inhibitor (C1-INH)
o Results in activation of kallikrein &
o ↑ formation of bradykinin
( ↑vascular permeability - recurrent episodes of
angioedema of airways, gastrointestinal tract,
extremities & genitalia)
 Treatment - drugs inhibiting formation or
actions of bradykinin

23. Kinin receptors & mechanisms of action
 G protein-coupled receptors
o B1 (bradykinin) – no subtype
o B2 (bradykinin) – subtypes B2A & B2B
 Bradykinin - highest affinity in most B2 receptor
systems, followed by Lys-bradykinin
 B1 receptors - in inflammatory response , collagen
synthesis & cell multiplication
 B2 receptors - calcium mobilization, chloride
transport, formation of nitric oxide, activation of
phospholipase C, phospholipase A2 & adenylyl cyclase

24. Drugs affecting kallikrein-
kinin system
 Icatibant
o Second-generation B2 receptor antagonist
o Absorbed rapidly - SC
o Treatment of hereditary angioedema
 Third generation of B2-receptor antagonists e.g.
FR 173657, FR 172357 & NPC2
o Orally active
o Reported to inhibit
 Bradykinin- induced bronchoconstriction in guinea pigs
 Carrageenin-induced inflammation in rats
 Capsaicin-2 - induced nociception in mice

25. Cont’d Drugs affecting
kallikrein-kinin system
Synthesis of kinins inhibited
 Kallikrein inhibitor – Aprotinin
 Human plasma C1-INH preparations - Cinryze &
Berinert (used for intravenous prophylaxis or
treatment of hereditary angioedema)
 Ecallantide –
o Recombinant plasma kallikrein inhibitor
o More potent & selective than C1-INH
o Administered by subcutaneous injection

26. VASOPRESSIN
Arginine vasopressin (AVP) , Antidiuretic hormone
(ADH)

27. VASOPRESSIN RECEPTORS
G protein coupled receptors
Characteristic V1a V1b V2
Location Vascular & other
smooth muscles,
platelets ,
hepatocytes
Anterior
pituitary
Colleting duct
cells of kidney ,
vascular
endothelium
Function Vasoconstriction ,
visceral smooth
muscle contraction
, platelet
aggregation
ACTH
release
Antidiuretic
action

28. Vasopressin receptor agonists
Vasopressin – V1/V2 receptor actions non
selective
Desmopressin
– t1/2 2 hrs
– action lasts for 10 hrs
- V2 receptor selective action
Terlipressin - V1>> V2 receptor selective action
Felypressin - V1 receptor selective action

29. Therapeutic uses -Vasopressin
receptor agonists
Based on V1 receptor action – Preferred drug terlipressin
1. Treat Bleeding of oesophageal varices
2. Treat post operative paralytic ileus
3. Prevent bleeding in acute haemorrhagic gastritis
Based on V2 receptor action – Preferred drug desmopressin
1. Diabetes insipidus
2. Primary nocturnal enuresis
3. To relieve post lumbar puncture headache

30. Vasopressin receptor antagonists
 Convaptan –
o First non peptide ADH receptor antagonist
o Approved for treatment of euvolaemic
hyponatremia (SIADH) & congestive heart
failure – ADH excess
o Disadvantages
 Requires IV administration
 Non selective action - V2 & V1a
 Cann’t be administered with CYP3A4 inhibitors
 Orally active V2 receptor selective , non
peptide antagonists approved recently –
Tolvaptan , relcovaptan , satavaptan &
mozavaptan

31. NATRIURETIC PEPTIDES
Parameters Atrial natriuretic
peptide (ANP)
Brain
Natriuretic
peptide (BNP)
C type
natriuretic
peptide (CNP)
Site of
synthesis
Cardiac atrial cells
, ventricular cells
,central &
peripheral neurons
, lungs
Ventricle Vascular
endothelium, CNS
, kidney ,
intestine
Factors
stimulating
release
Atrial stretch ,
volume expansion ,
endothelins , heart
failure , primary
aldosteronism
Volume
expansion
Unclear

32. NATRIURETIC PEPTIDES
Parameters Atrial
natriuretic
peptide (ANP)
Brain Natriuretic
peptide (BNP)
C type
natriuretic
peptide (CNP)
Actions Natriuresis ,
diuresis ,
↓ arterial BP
(vasodilatation)
Natriuresis ,
diuresis ,
↓ arterial BP
(vasodilatation)
Vasodilator ;
lesser
natriuretic &
diuretic
Uses Diagnostic /
prognostic
marker in heart
failure
- Synthetic form
nesiritide is used
for CHF
Nil
Pharmacokinet
ics
Shorter t1/2
Metabolised neutral endopeptidase( NEP – 24.11)
Removed by binding to ANPc receptors

33. Characteristics ANPA ANPB ANPC
Location On surface of
target cells
On surface of
target cells
Vascular
endothelium
Ligand ANP + BNP CNP ANP + BNP +
CNP
Natriuretic peptide receptors

34. Clinical role of natriuretic peptides
 Recombinant ANP (carperitide ) or BNP
(nesiritide)
o Clinical studies in treatment of congestive heart failure
have produced variable results
 Vasopeptidase (Neutral endopeptidase +
angiotensin converting enzyme) inhibitors -
omapatrilat, sampatrilat & fasidotrilat
o Lowers BP - Animal models of hypertension & Hypertensive
patients
o Improves cardiac function in heart failure
o Causes angioedema , cough & dizziness
o Not approved for clinical use

35. ENDOTHELINS
Biosynthesis, Structure, & Clearance
 Three isoforms -ET-1, ET-2 & ET-3
 ET-1 - predominant endothelin
o vascular endothelium , brain & kidney
 ET-2 produced - kidneys & intestine
 ET-3 found in highest concentration in brain ,
gastrointestinal tract, lungs & kidneys

36. Characteristi
c
ETA ETB
Location Vascular smooth muscle
, brain , lungs , kidney ,
adrenal gland
Vascular endothelium ,
brain , intestine ,
kidney , adrenal gland
G – protein coupled
Function Vasoconstriction ,
bronchoconstriction &
aldosterone secretion ,
mitogenesis
Vasodilatation ,
mitogenesis
Agonist ET1 > ET2 > ET3 ET1 = ET2 = ET3
Antagonist Bosentan , Sitaxsentan &
Ambrisentan
Bosentan

37. Inhibitors of endothelin synthesis & action
 Bosentan
o Active orally – Treatment of pulmonary hypertension
 Ambrisentan & sitaxsentan- Approved by FDA to
Treat pulmonary artery hypertension
 Macitentan
o Dual endothelin receptor antagonist
o approved by FDA
o ↑ efficacy in pulmonary hypertension compared with
other antagonists & well tolerated with fewer side
effects
 Inhibitor endothelin converting enzyme -
phosphoramidon

38. Physiologic & Pathologic Roles of Endothelin:
Effects of Endothelin Antagonists
 Systemic administration - ER antagonists or endothelin-
converting enzyme inhibitors → vasodilation & ↓ arterial
pressure
 Activity of system is
o Higher in males than in females
o ↑ with age - can be counteracted by regular aerobic exercise
 ↑ production of ET-1 implicated in
o CVS diseases (hypertension , cardiac hypertrophy, heart
failure, atherosclerosis, coronary artery disease & myocardial
infarction)
o Pulmonary diseases (asthma , pulmonary hypertension; renal
diseases; several malignancies -ovarian cancer)
Endothelin antagonists - potential for treatment of these
diseases

39. VASOACTIVE INTESTINAL
PEPTIDE
 Belongs to glucagon-secretin family
 Distributed in
o CNS (neurotransmitter or neuromodulator)
o Peripheral nervous systems (peptide
neurotransmitters)
 Significant effects on CVS
o Causes coronary vasodilation & exerts +
inotropic & chronotropic effects

40. Cont’d VASOACTIVE
INTESTINAL PEPTIDE
 Effects mediated by
o VPAC1 & VPAC2 (G protein coupled receptors)
o Distributed in CNS & in heart, blood vessels &
other tissues
 Potential as therapeutic agents for cardiovascular,
pulmonary, gastrointestinal & nervous system diseases
(Alzheimer ’s & Parkinson’s disease )
 Use is currently limited by several issues including
poor oral availability & hypotension

41. SUBSTANCE P
 Belongs to tachykinin family
 Present in
o CNS- neurotransmitter (behavior, anxiety,
depression, nausea & emesis)
o Gastrointestinal tract - transmitter in enteric
nervous system & local hormone
o Peripheral afferent pain fibers
o CVS - Potent arteriolar vasodilator (release of
nitric oxide from endothelium) – marked
hypotension

42. Cont’d SUBSTANCE P
 Actions mediated - Gq protein-coupled tachykinin receptors
(NK1, NK2, and NK3)
 Recent clinical trials - antagonists useful in
o Treating depression
o Preventing chemotherapy – Induced emesis
Aprepitant - approved
Fosaprepitant – prodrug of aprepitant
 Recent studies implicated substance P-NK1 system in
cancer
o Present in variety of tumor cells
o NK1 receptor antagonists exert an antitumor action
o Aprepitant - potential as anti-cancer agents

43. NEUROTENSIN
 Tridecapeptide
Dual function
 CNS - Neurotransmitter or neuromodulator
o Hypothermia
o Antinociception
o Modulation of dopamine & glutamate neurotransmission
(schizophrenia, Parkinson’s disease & drug abuse)
 Central administration of NT produces effects in
rodents similar to those produced by antipsychotic
drugs

44.  Peripheral circulation - Local hormone
o Vasodilation, hypotension, ↑ vascular permeability
o ↑ secretion of several anterior pituitary hormones
o Hyperglycemia
o Inhibition of gastric acid , pepsin secretion, gastric
motility
 NT receptors -
o NTR1, NTR2 & NTR3 (NTS1 , NTS2 & NTS3)
o Gq protein-coupled superfamily
 Neurotensin receptor agonist – PD149163
crosses BBB- undergoing clinical trial as
antischizophrenic & antiparkinsonism drug

45. CALCITONIN GENE-
RELATED PEPTIDE
 Member of calcitonin family of peptides (calcitonin,
adrenomedullin & amylin)
 Present in
o C cells of thyroid gland
o Central & peripheral nervous systems
o Cardiovascular ,Respiratory systems & Gastrointestinal tract
 Actions mediated
o Single heterodimeric receptor
o G protein coupled Calcitonin receptor-like receptor (CLR)
combined with receptor activity-modifying protein RAMP1

46. Cont’d CGRP
 Effects produced when Injected into
o Central nervous system - hypertension &
suppression of feeding
o Systemic circulation - hypotension &
tachycardia
 Evidence
o Release of CGRP from trigeminal nerves
plays a central role in pathophysiology of
migraine
o Peptide is released during migraine attacks
o Successful treatment of migraine - selective
serotonin agonist normalizes cranial CGRP
levels
Clinical trials showed CGRP antagonists
Olcegepant –
1. effective in treating migraine
2. low bioavailability - administered by IV route
Telcagepant
effective , orally active ,exhibited liver toxicity

47. ADRENOMEDULLIN (AM)
 Found in adrenal glands, hypothalamus, anterior
pituitary, kidneys, lungs, cardiovascular system,
gastrointestinal tract
 In animals, AM dilates resistance vessels in
kidney, brain, lung, hind limbs & mesentery -
long-lasting hypotension
 Functions as a physiologic antagonist of actions
of vasoconstrictors (ET-1 and ANG II )

48. Cont’d AM
 AM receptor - CLR co-assembles with RAMP
subtypes 2 & 3
o Activates Gs
o Triggers cAMP formation in vascular smooth
muscle cells
o ↑ nitric oxide production in endothelial cells
 Plasma AM levels
o ↑ during intense exercise
o ↑ in essential & pulmonary hypertension, acute
myocardial infarction, cardiac & renal failure
o ↑ in proportion to severity of these diseases & this
can be a useful prognostic marker
May protect against cardiovascular overload & injury

49. NEUROPEPTIDE Y
Multiligand/multireceptor system
Three polypeptide agonists
o Pancreatic polypeptide (PP)
o Peptide YY (PYY)
o Neuropeptide Y (NPY)

50. Neuropeptide Y (NPY)
 Abundant - central & peripheral nervous systems
(Neurotransmitter)
 CNS effects
o ↑ feeding (one of most potent orexigenic molecules in
brain)
o Hypotension, hypothermia
o Respiratory depression
o Activation of hypothalamic pituitary-adrenal axis
 Other Effects
o Vasoconstriction of cerebral blood vessels,
o + chronotropic & inotropic actions on heart
o Hypertension
o Potent renal vasoconstrictor
o Suppresses renin secretion

51. Cont’d Neuropeptide Y (NPY)
 Effects of NPY (and PP and PYY) mediated by NPY
receptors : Y1,Y2,Y4 & Y5
o Gi protein-coupled receptors
o Y1& Y2 receptors - major importance in cardiovascular
& other peripheral effects
 Y4 receptors - high affinity for pancreatic
polypeptide
 Y5 receptors –
o Central nervous system
o May be involved in control of food intake
o Mediate activation of hypothalamic-pituitary-adrenal
axis by NPY

52. Cont’d Neuropeptide Y (NPY)
 First nonpeptide Y1 receptor antagonist,
BIBP3226
o short half-life in vivo.
o in animal models, it blocks vasoconstrictor &
pressor responses to NPY
 SR120107A & SR120819A
o Orally active Y1 antagonists
o Long duration of action
 Y5 antagonists - MK-0557 & S-2367 -
tested in clinical trials for obesity
Studies have implicated NPY in
eating disorders,obesity,
alcoholism,
anxiety,depression, epilepsy,
pain, cancer
Y1 & Y5 receptor antagonists - potential as
antiobesity agents.

53. uROTENSIN
 UII - potent constrictor of vascular smooth muscle
 Actions - Gq protein-coupled receptor (UT receptor)
 Palosuran -nonpeptide antagonist – benefit diabetic
patients with renal disease but lacks potency
 More potent UII antagonists are in phase 1 clinical trials,
o EP2439193 - treatment of diabetic nephropathy
o SB1440115 - treatment of asthma

54. Conclusion
Knowledge of vasoactive peptides can help us to
identify newer potential targets in treating various
CNS diseases like
Anxiety
Depression
Schizophrenia
CVS diseases like
Resistant hypertension
Congestive heart failure
Left ventricular dysfunction
Obesity ;
which are difficult to treat in present scenario.

55. references
 Katzungs Basic & Clinical Pharmacology
13th edition by Bertram G. Katzung &
Anthony J. Trevor
 Principles of Pharmacology 2nd edition by
HL Sharma & KK Sharma

57. Major physiologic inputs to renin release and proposed integration with signaling pathways in the
juxtaglomerular cell. AC, adenylyl cyclase; ANG II, angiotensin II; ANP, atrial natriuretic peptide; cGK,
protein kinase G;DAG, diacylglycerol; GC-A, particulate guanylyl cyclase; ER, endoplasmic reticulum; IP,
inositol trisphosphate; NE, norepinephrine; NO, nitric oxide; PDE, phosphodiesterase; PKA, protein kinase
A; PLC, phospholipase C; sGC, soluble 3guanylyl cyclase.X

58. Prorenin Receptors
 receptor that preferentially binds prorenin has been
identified. Since it also binds active renin, the receptor
is referred to as (pro)renin receptor
 Recent research indicates that the (pro)renin receptor
is functionally linked to the vacuolar proton-ATPase
(ATP6ap2) and is necessary for Wnt signaling pathways
involved (independently of renin) in stem cell biology,
embryology, and cancer.

59. KININS
BIOSYNTHESIS OF KININS
Kallikreins
serine proteases present in
 plasma - plasma kallikrein - activated by Factor XIIa
 several organs - tissue kallikrein ( kidneys, pancreas,
intestine, sweat glands & salivary glands)
kininogens
kallikreins • enzymes
Kinins • vasodilator
peptides

60. Kininogens
 Substrates for kallikreins
 Precursors of kinins—present in plasma, lymph &
interstitial fluid
 Kininogens present in plasma :
 Low-molecular-weight form (LMW kininogen) - tissue
kallikreins
 High-molecular-weight form (HMW kininogen)- plasma
kallikrein

61.  UT receptors distributed in the
 brain, spinal cord,
 heart,vascular smooth muscle,
 skeletal muscle, and
 pancreas
 Effects of peptide including vasoconstriction mediated by
 phospholipase C,
 inositol trisphosphate,
 diacylglycerol signal transduction pathway
 plasma UII levels are ↑ in
 hypertension,
 heart failure,
 atherosclerosis,
 diabetes mellitus, and
 renal failure.

62. Generation of endothelin-1 (ET-1) in the vascular endothelium, and its direct
and indirect effects on smooth muscle cells mediated by ETA and ET
receptors. ANG II, angiotensin II; ANP, atrial natriuretic peptide; Arg,
arginine;BigET-1, proET-1; ECE, endothelial- converting enzyme; NO, nitric
oxide; PreproET-1, precursor of BigET-1; PGI B
,prostaglandin I2

63. Angiotensinogen
 Synthesized in liver
 Production of angiotensinogen - ↑ by corticosteroids,
estrogens, thyroid hormones & ANG II
 ↑ plasma angiotensinogen concentration - hypertension
Angiotensin I
 little or no biologic activity

64. Converting Enzyme (ACE, Peptidyl Dipeptidase, Kininase
II)
 ANG I → ANG II, & bradykinin, which it inactivates
 Located on luminal surface of vascular endothelial cells & close contact
with circulation
Angiotensinase
Angiotensin II - plasma half-life of 15–60 seconds, removed
rapidly from circulation by peptidases - angiotensinase

65. Cont’d Drugs affecting
kallikrein-kinin system
SSR240612
 New, potent & orally active - Selective
antagonist of B1 receptors
 Exhibits analgesic & anti-inflammatory
activities in mice & rats
 Currently in preclinical development for
treatment of inflammatory & neurogenic
pain