1. Peptides Autacoids
Dr Mahmoud Khattab

2. 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

3. Renin Release Renin release is stimulated by:
Β1-adrenergic stimulation
Decreased BP/Blood
Volume, Renal Ischemia,
Sodium Depletion
Drugs: ACEIs, ARBs
Diuretics, Vasodilators
Renin release is
inhibited by: NSAIDs,
Β-adrenergic blockers

4. 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)

5. Actions of ACE

6. 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

7. Angiotensin II Receptors
Two main receptors are identified: Type-1 & Type-2 angiotensin II receptors
Both are G-protein coupled receptors
Type-1
Type-2
Agonist
AngII>AngIII
AngII=AngIII
Antag.
Losartan
__________
Trans-duction
- Gq-PLC-IP3
- Gi-AC-c.AMP
Phosphotyrosine phosphatase

8. Angiotensin II Type-1 Receptor Distribution & Function
Physiologic functions of AT1 receptors according to their location
LOCATION
FUNCTION
Kidney
Glomerulus
Mesangial cell contraction
Proximal tubule
Increased re-absorption of sodium
Juxtaglomerular apparatus
Decreased renin secretion
Heart
Inotropic effect and release of growth factors with ensuing stimulation of cardiac myocyte hypertrophy and increased extracellular matrix production
Blood vessels
Vasconstriction with an increase in afterload as well as local release of growth factors
Adrenal gland
Aldosterone and catecholamine release
Brain
Vasopressin release, stimulation of thirst; autonomic activity and cardiovascular reflexes
Sympathetic nervous system
Increased sympathetic outflow

9. 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

10. 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

11. 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

12. 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

13. 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

14. Renin-Angiotensin-Aldosterone System (RAAS) Antagonists
Angiotensin 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)

15. RAAS Antagonists Angiotensin 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)

16. Therapeutic Uses & Adverse Effects
RAAS Antagonists Angiotensin 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

17. RAAS Antagonists Angiotensin 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

18. RAAS Antagonists Vasopeptidase 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 nephropathy
Renin Inhibitors
Enalkiren & ditekiren are inhibitors of renin
They lower BP hypertensive subjects
They are still investigated

19. 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

20. 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)

21. Kinins Receptors, 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)

22. Kinins Actions & 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

23. Endothelium-Derived Contracting Factor (EDCF)
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

24. 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

25. 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%)

26. 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