Peptides Autacoids

Dr Mahmoud Khattab

Angiotensins, Angiotensin II, and Blockers

The renin-angiotensin (Ang)-aldosterone system (RAAS) has vital pathophysiological & therapeutic importance

Angiotensins peptides derived from a high-molecular weight angiotensinogen, a plasma 2-globulin

Renin, released from the kidneys & others, converts angiotensinogen into a the decapeptide, angiotensin I (AngI, inactive)

Angiotensin-converting enzyme (ACE, peptidyly dipeptidase, kiniase), found in plasma & tissues including glands, kidneys, endothelium & heart

Renin Release

Renin release is stimulated by: Β1-adrenergic stimulation Decreased BP/BloodVolume, Renal Ischemia, Sodium Depletion o Drugs: ACEIs, ARBsDiuretics, Vasodilators Renin release is inhibited by: NSAIDs,Β-adrenergic blockers

Angiotensins, Angiotensin II, and Blockers

ACE cleaves two carboxy terminal amino acids (9 and 10) of AngI to form the octapeptide AngII, the most active form

AngII is converted to a less active heptapeptide AngIII & other inactive fragments by a carboxy-peptidase

A new homolog of the enzyme, "ACE2" was identified

AngI/AngII are substrates for the enzyme, the products are the nonapeptide Ang-(1-9), or a heptapeptide Ang(1-7)

Actions of ACE

Metabolism of Angiotensin Peptides

Ang II can be converted to the heptapeptide Ang III by glutamylaminopeptidase or to ang (1-7) by prolylendopeptidase

Ang III generally is less potent than ang II but is equally potent as a stimulator of aldosterone secretion

Ang III can be metabolized to a hexapeptide (ang 3−8, ang IV) fragment by an arginylaminopeptidase

Ang IV is currently being studied as a biologically active peptide with potential physiologic significance

Angiotensin II Receptors

Two main receptors are identified: Type-1 & Type-2 angiotensin II receptors

Both are G-protein coupled receptors

Type-1Type-2

AgonistAngII>AngIIIAngII=AngIII

Antag.Losartan__________

Trans-duction

- Gq-PLC-IP3

- Gi-AC-c.AMP

Phosphotyrosine phosphatase

LOCATIONFUNCTION

Kidney

GlomerulusMesangial cell contraction

Proximal tubuleIncreased re-absorption of sodium

Juxtaglomerular apparatusDecreased renin secretion

HeartInotropic effect and release of growth factors with ensuing stimulation of cardiac myocyte

hypertrophy and increased extracellular matrix production

Blood vesselsVasconstriction with an increase in afterload as well as local release of growth factors

Adrenal glandAldosterone and catecholamine release

BrainVasopressin release, stimulation of thirst; autonomic activity and cardiovascular reflexes

Sympathetic nervous systemIncreased sympathetic outflow

Angiotensin II Type-1 Receptor Distribution & Function

Physiologic functions of AT1 receptors according to their location

AT-1 Receptor-Mediated Actions of Angiotensin II

Vasculature: Vascular hypertrophy Potent vasoconstriction of pre- & post-capillary

blood vessels in skin, kidney & splanchnic areas (minor in brain & skeletal muscle)

Cardiac hypertrophy & fibrosis, positive inotropy Increased NE release from sympathetic nerve

terminals, adrenal medulla & brain (indirect vasoconstriction)

Aldosterone release from adrenal cortex Antdiuretic hormone (ADH, vasopressin) release

from pituitary gland

Paracrine Renal Effects of Angiotensin

AngI (AI) is generated in the afferent arteriole, converted to ang II (AII) by ACE AII can cause mesangial cell contraction & efferent arteriolar constriction AII can also be filtered at the glomerulus & subsequently act at the proximal

tubular cells to increase sodium re-absorption In the renal interstitium, renin produces angiotensin peptides that act at

vascular and tubular structures Angiotensin peptides may also be synthesized in and released from renal

juxtaglomerular cells

AT-2 Receptor-Mediated Actions of Angiotensin II

Release of bradykinin Production of nitric oxide, and increased cGMP Vasodilation Antiproliferative effect on vascular smooth and

cardiac muscles Stimulation of Apoptosis Cell differentiation

The Natriuretic Peptide Family

Include atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP)

ANP derived from a 126 amino acids prohormone, secreted primarily from cardiac atria

BNP, identified initially in brain, is secreted from both atria & ventricles

CNP identified in brain & in vascular endothelial cells

Stretch receptors in the atria and ventricles detect changes in cardiac chamber volume related to increased cardiac filling pressures, resulting in release of both ANP and BNP but not CNP

The Natriuretic Peptide Family

The actions of the natriuretic peptides are mediated by natriuretic peptide receptors (NPRs), NPR-A/B/C

NPR-A & NPR-B are coupled to membrane-bound GC, increases levels of cGMP

NPRs are localized in vascular SM, endothelium, platelets, the adrenal glomerulosa, & the kidney

ANP & BNP increase urine volume & sodium excretion, decrease vascular resistance, and inhibit release of renin and secretion of aldosterone & vasopressin

Neutral endopeptidases (NEPs) inactivate NPs

Renin-Angiotensin-Aldosterone System (RAAS)

AntagonistsAngiotensin Converting Enzyme Inhibitors (ACEIs)

SH- compounds: captopril, zofenopril, pivalapril Carboxyl compounds: benazepril, cilazapril, enalapril,

lisinopril, perindopril, quinapril, ramipril Phosphoryl compounds: fosinpril, ceronapril

Mechanism & Site of Action: Competitive inhibition of ACE, being structural analogs to

the di-peptides cleaved by the enzyme In exp animals & humans, they inhibit the pressor effect of

IV angI denoting inhibition of conversion to angII Inhibition of bradykinin degradation by ACE leading to

increased kinins levels (both therapeutic & side effect)

RAAS AntagonistsAngiotensin Converting Enzyme Inhibitors

(ACEIs) Main Effects

Reduced formation of ang II leading to inhibition of most AT-1 receptor-mediated actions

Reduction of direct angII-induced vasoconstriction Inhibition of angII-mediated sympathetic NS

stimulation that might contribute to vasodilation Significant reduction of plasma aldosterone levels

leading to hyperkalemia & sodium depletion Reduced vasopressin release→ increased water

depletion (enhance diuretic effect)

RAAS AntagonistsAngiotensin Converting Enzyme Inhibitors

(ACEIs) Main Effects Increased levels of bradykinin → increased

vasodilatation & induction of cough & itching Increased plasma renin activity as a result of

impaired angII-mediated feedback inhibition

Therapeutic Uses & Adverse Effects

Main uses are treatment of hypertension (HTN) & CHF, discussed later in respective lectures

Detailed actions in HTN & CHF, and adverse effects, are to be discussed later with Prof Matrafi under respective topics

RAAS AntagonistsAngiotensin II Type-1 (AT-1) receptor

Antagonists They are competitive antagonists at AT-1

receptors with only low affinity to AT-2 R They include drugs like losartan & valsartan They block AT-1-mediated actions, similar to

ACEIs but: No effect on bradykinin, substance P, ACE Feedback inhibition of angII is blocked→ ↑ renin

release → increased angII Detailed actions in HTN & CHF, and adverse

effects, are to be discussed later with Prof Matrafi under respective topics

RAAS AntagonistsVasopeptidase Inhibitors

Dual inhibitors of ACE & neutral endopeptidase Examples: omapatrilat & ilepatril (Sanofi-Aventis

Pharma) They decrease circulating angIi and increase

levels of ANP and bradykinin They under clinical trials for treatment of

hypertension, CHF, and diabetic nephropathyRenin Inhibitors

o Enalkiren & ditekiren are inhibitors of renino They lower BP hypertensive subjectso They are still investigated

Kinins

Bradykinin is an endogenous vasodilator nonapeptide, released from plasma α2-globulins kininogens

High molecular weight (HMW) form present in plasma & a low molecular weight (LMW) form present in tissues

Hydrolysis of plasma HMW kininogen, by plasma kallikrein, a protease, gives bradykinin

Kinins

Hydrolysis of LMW kininogen by tissue kallikrein →kallidin Kallidin a vasodilator decapeptide with similar properties to

those of bradykinin Bradykinin is cataboloised by kiniase II, identical to

peptidyl dipeptidase (ACE)

KininsReceptors, Actions & Therapy

The activate B1, B2, B3 receptors linked to PLC/A2

Powerful Vasodilation→ decreased blood pressure via B2 receptor stimulation (NO-dependent)

Increase in capillary permeability inducing edema.It produces inflammation & algesia (B2)

Cardiac stimulation: Compensatory indirect & direct tachycardia & increase in cardiac output

It produces coronary vasodilation

Bradykinin has a cardiac anti-ischemic effect, inhibited by B2 antagonists (NO & PI2 dependent)

KininsActions & Therapy

Kinins produce broncho-constriction & itching in respiratory system (antagonized by ASA)

Therapeutic Use: No current use of kinin analogues Increased bradykinin is possibly involved in the

therapeutic efficiency & cough produced by ACEIs Aprotinin (Trasylolol), a kallekrein inhibitor, used

in treatment of acute pancreatitis, carcinoid syndrome & hyperfibrinolysis

Endothelins

Vascular Endothelium

↓Endothelium-Derived Contracting

Factor (EDCF)(De Mey & Vanhoutte, 1982)

↓Peptidergic EDCF (Hickey Et al., 1985)

↓A 21-Amino Acid Peptide, Endothelin-1

(Yanagisawa et al., 1988

Endothelin Receptors

ETA Receptors Agonist: ET-1=ET-2>ET-3 Smooth muscles Actions: Contractile activity Vasopressor response Aldosterone release

ETB Receptors Agonist: ET-1=ET-3 Smooth & endothelial

cells Actions: Initial depressor effect Initial relaxant response Ex vivo platelet inhibition ETB receptors located on

endothelium mediate NO- & PGI2-dependent vasodilatation

Endothelin Therapeutic Potential

Endothelin-based therapy is

Investigated for HTN, CHF Bosentan is a dual

ETA/ET B receptor antagonist Receptor affinity ratio (ET A /ET B ) of 20:1, enhancing

vasodilatory role in PAH by reducing ET A receptor activation

Bosentan reduces vascular remodeling Adverse Effects: Elevated liver enzymes headache (22%), nasopharyngitis (11%), flushing (9%),

hepatic function abnormality (8%) and lower extremity oedema (8%)

Substance P

Substance P is an undecapeptide present in brain, afferent neurons, dorsal horn of spinal cord

It plays a role in pain transmission It is present in intestine It activates substance P GPCRs linked to EDHF It produces vasodilation & contracts SM of GIT MK-869 is a substance P antagonist tested for

treatment of chemotherapy-induced emesis