Transcript PEPTIDES - Yeditepe University

PEPTIDES
• Tissue damage, allergic reactions, viral infections and
other inflammatory events activate a series of proteolytic
rections that generate BK and KD in the circulation or
tissues
• Kinin metabolites released by basic carboxypeptidases
are B1 rec agonists (binds des-Arg metabolites of kinins)
B1 receptors are xpressed by tissue injury and
inflammation. These peptides contribute to inflammatory
responses as autacoids that act locally to produce pain,
vasodilation and increased vascular permeability but
also have beneficial effects in the heart kidney and
circulation, PG NO EDRF
KALLIKREIN-KININ & RENIN
ANGIOTENSIN SYSTEMS
Vasoconstrictors
• Angiotensin II
• Vasopressin
• Endothelins
• Neuropeptide Y
• Urotensin
VASODILATORS
• Bradykinin and related kinins
• Natriuretic peptides
• Vasoactive intestinal peptide
• Substance P
• Neurotensin
• Calcitonin gene related peptide
• Adrenomedullin
PHARMACOLOGY OF KININS
• Understanding the roles of kinins have
advanced because generation of B1 and
B2 receptor knockout mice, also
availability of specific receptor antagonists
DEGRADATION OF BRADYKININ
• Pain
• Powerful algesic agents, BK excites
primary sensory neurons and provokes the
release of neuropeptides SP, NKA
calcitonin gene related peptide
• B2→acute BK algesia
• B1→pain of chronic inflammation
• Inflammation
• Plasma kinins ↑ permeability in the
microcirculation acting on the small
venules to cause disruption of the interendothelial junctions
• Edema results because of this + increased
hydrostatic pressure
• Respiratory disease
• Kinins play roles in asthma and rhinitis
• BK induced bronchoconstriction is blocked
by Anticholinergic agents but not by
Antihistamines or COX inhib.
• CV
• Vasodilation, ↓ bp
B2 rec on
endothelial
cells NO,
PGI2
• Kidney
• Regulate urine volume and composition
• ↑ renal blood flow, natriuresis
ANGIOTENSIN
Angiotensin I is released from angiotensinogen by
enzymatic cleavage and renin catalyzes this
reaction.
Angiotensin (Ang) converting enzyme stimulates
conversion of AngI to AngII
Degradation of AngII is accomplished by several
peptidases.
RENIN ANGIOTENSIN SYSTEM
Renin is an aspartyl protease that specifically
catalyzes the hydrolytic release of the
decapeptide Ang I from angiotensinogen.
Renin in the circulation originates in the kidneys.
Enzymes w renin-like activity are present in
several extrarenal tissues.
Renin secretion is controlled by a variety of
factors, including
• a renal vascular receptor
• the macula densa
• the sympathetic nervous system
• angiotensin
• pharmacologic alteration of renin release
ACTIONS OF ANGIOTENSIN II
Ang II exerts important actions at several sites in
the body, including vascular smooth muscle,
adrenal cortex, kidney and brain.
Through these actions, the renin-Ang system plays
a key role in the regulation of fluid and
electrolyte balance and arterial blood pressure.
Xessive activity of the renin-ang system can result
in hypertension and disorders of fluid and
electrolyte homeostasis.
BLOOD PRESSURE
Ang II is a very potent pressor agent-on a molar
basis, ~40 times more potent than NE.
The pressor response to iv Ang II is rapid in onset
10-15 seconds and sustained during long-term
infusion of the peptide
A large component of pressor response to iv Ang II
is due to direcxt contraction of vascularespecially arteriolar-smooth muscle.
In addition, Ang II can also increase bp through
actions on the brain and autonomic nervous
sytem. The pressor response to angiotensin is
usually accompanied by little or no reflex
bradycardia because the peptide acts on the
brain to reset the baroreceptor reflex control of
heart rate to a higher pressure.
Ang II also interacts w the autonomic nervous
system. It stimulates autonomic ganglia,
increases the release of E and NE from the
adrenal medulla, and facilitates sympathetic
transmission by an action at adrenergic nerve
terminals.
Adrenal Cortex Ang II acts directly on the zona
glomerulosa of the adrenal cortex to stimulate
aldosterone biosynthesis. At higher
concentrations, Ang II also stimulates
glucocorticoid biosynthesis.
Kidney Causes renal vasoconstriction, increase
proximal tubular Na reabsorption, and inhibit
secretion of renin.
CNS Ang II acts on the CNS to stimulate drinking
(dipsogenic effect) and increase the secretion of
vasopressin and adrenocorticotropic
hormone(ACTH).
Cell growth Ang II is mitogenic for vascular and
cardiac muscle cells and may contribute to the
development of CV hypertrophy. ACE inhibitors
and Ang II receptor antagonists prevent
morphologic changes (remodeling) following MI.
Ang II receptors are widely distributed in the body.
Like the receptors for other peptide hormones,
ang II receptors are located on the plasma
membrane of target cells, and this permits rapid
onset of the various actions of Ang II.
Two distinct subtypes of Ang II receptors are AT1
and AT2
AT1 receptors predominate in vascular smooth
muscle
AT2 receptors are present at high density in all
tissues during fetal development, they are much
less abundant in the adult where they are
expressed at high conc only in the adrenal
medulla , reproductive tissues, vascular
endothelium and parts of the brain.
AT1 receptors have a high affinity for losartan and
a low affinity for PD 123177(an experimental
nonpeptide antagonist)
While AT2 receptors have a low affinity for losartan
and a high affinity for PD 123177
Ang II and saralasin bind equally to both subtypes.
INHIBITORS OF RENIN-ANG
SYSTEM
Drugs that block renin secretion
Aliskiren, Clonidine, propranolol are such drugs.
CONVERTING ENZYME
INHIBITORS
Captopril and enalapril are such drugs.
They decrease systemic vascular resistance
without increasing heart rate, and they promote
natriuresis.
They are effective in the treatment of hypertension,
decreae morbidity and mortalityin heart failure
and left ventricular dysfunction after myocardial
infarction.
ACE inhibitors not only block the conversion of
Ang I to angiotensin II but also inhibit the
degradation of other substances, including
bradykinin, substance P and enkephalins. The
action of ACE inhibitors to inhibit BK metabolism
contributes significantly to their hypotensive
action and also responsible for some adverse
effects, including cough and angioedema.
In such cases Angiotensin receptor antagonists
might be chosen (class discussion)
ANGIOTENSIN ANTAGONISTS
Substitition of sarcosine for the Phenylalanine in
position 8 of Ang II results in the formation of
potent peptide antagonists of the action of Ang II.
Saralasin is the name of the compound. Must be
adm iv
Nonpeptide antagonists are of much greater
interest
Losartan and valsartan, eprosartan, irbesartan,
candesartan, and telmesartan are AT1
antagonists used in the treatment of
hypertension without the adverse effects of ACE
inhibitors