By Duy Thai, 1997 Pharmacology Semester 1 page 1 of 4

PERIPHERAL PEPTIDE HORMONES

• Low molecular weight transmitters

• Noradrenaline
• Adrenaline
• Neuropeptides
• Substance P (pain transmission)
• Opiods (pain modulation)
• Vasoactive peptides (hormones)
• Angiotensin (BP control)
• Bradykinin

ANGIOTENSIN II

The renin angiotensin system

• The R-A system is involved in homeostatic control of blood pressure and fluid and electrolyte balance.
• If there is a decrease in blood pressure and/or Na in the blood, various autonomic reflexes are enabled to bring
things back to normal.
• A fall in blood pressure causes the baroreceptors to activate sympathetics
• Sympathetic activation causes increased cardiac output and peripheral vasoconstriction.
• Sympathetic nerves innervating the kidney stimulates the release of renin from the juxtaglomerular cells
(beta 1 receptor).
• The release of renin is also mediated by:
• The afferent arteriole sensing a decrease in stretch (less blood flow)
• The macula densa sensing a decreased Na load.

• Renin cleaves angiotensinogen to angiotensin I.

• Angiotensin I is converted to angiotensin II via Angiotensin converting enzyme (ACE) found in the lungs.
• Angiotensin II has many diverse effects, all leading to an increase in blood pressure and sodium retention.

Actions of angiotensin II
1. Immediate effects:
• Increasing peripheral resistance via:
A. Vasoconstriction (arteries > veins)
B. Enhancing NA release from sympathetic neurons
2. Intermediate effects:
• Effects on renal function (fluid balance control):
A. Stimulating aldosterone release
• Increase in sodium reabsorption
B. Renal hemodynamics
• Angiotensin II can act directly to cause Na reabsorption
• AII also causes vasoconstriction of the efferent arteriole > afferent arteriole to increase
GFR
3. Long term effects
• Effects on cardiovascular structure:
A. By increasing peripheral resistance, there is an increase in afterload. The heart thus has to pump
harder, resulting in hypertrophy
B. AII is also mitogenic, stimulating cardiac muscle growth
• Long term effects may be related to a more chronic rise in blood pressure (possibly leading to
hypertension)

Receptors
• AT1
• AT2

• Most of the effects of Angiotensin II are via the AT1 receptor. Currently, there is no functional role for the AT2
receptor.
By Duy Thai, 1997 Pharmacology Semester 1 page 2 of 4

Therapeutic use of renin angiotensin system inhibitors

• All these drugs are effective antihypertensive agents

1. Drugs acting on the receptor

• Saralasin
• A peptide, hence can't be taken orally
• A partial agonist
• When AII concentrations are low, we see an increase in blood pressure as saralasin is
acting to mimic the effects of angiotensin II
• However, when AII concentrations are high, it acts as a antagonist because it prevents
AII from exerting its full effects.
• Lorsatin
• A non peptide drug, therfore better absorbed
• Selective AT1 antagonist
• Why do we need another antihypertensive drug? Aren't beta blockers good enough?
• The problem with beta blockers is that they may be a problem for some people, e.g.
asthmatics. A beta1 blocker (e.g. atenolol) can be used to inhibit the release of renin
but atenolol is only selective for beta1 at a certain concentration. Above this, it can act
on beta2 receptors. If beta2 receptors in the bronchi are blocked, you can get a
bronchoconstricton.

2. Drugs acting on renin release

• Substrate analogues of angiotensinogen to bind to renin and prevent angiotensinogen from binding. Not
useful
• Beta1 adrenoreceptor antagonists (Atenolol)

3. Drugs acting on ACE (very effective)

• Captopril
• An analogue of angiotensin I
• Binds to ACE and prevents angiotensin I from being converted to angiotensin II.
• Can be taken orally
• Very goo antihypertensive
• The only problem is that it has a short half life (4 - 8 hrs)
• Enalapril
• The inactive prodrug which is given orally
• In the body, it is converted to Enalaprilate
• Enalaprilate is a modified tripeptide which acts in a similar way to captopril. It has the
advantage however, of having a longer half life (needs to be taken once daily)
• These drugs are also effective in congestive heart failure where there is cardiac hypertrophy.
• Side effects:
• Dry cough, loss of taste
• Angioedema (excess fluid in the vascular wall)
• ACE is not a selective enzyme. It can also involved in the synthesis of substance P and
the breakdown of bradykinin. Inhibition of ACE can thus cause decreased substance P
and increased bradykinin.
• A decrease in substance P can cause the dry mouth and cough (because substance P is
involved in salivary and mucous secretion.)
• An increase in bradykinin results in the angioedema
• If lorsartin works, it will prevent these problems beacuse it is acting on a specific receptor which
is only used by angiotensin II, hence no overlap of functions.

THE KININS

• Kinins are local mediators of pain and inflammation

• The kinins are a family of small peptide molecules which include:
• Bradykinin
By Duy Thai, 1997 Pharmacology Semester 1 page 3 of 4

• Kallidin
• des Arg9 Bradykinin

Synthesis of kinins
1. Kinins are produced in response to tissue damage
2. Tissue damage causes the activation of Hageman factor which is involved in the clotting mechanism.
3. Hageman factor converts plasma prekallikrien to plasma kallikrein.
• Kallikreins are enzymes which break down kininogens (the precursors of kinins)
• There are 2 forms of kallikreins:
• Plasma kallikrein
• Tissue kallikrein (found in the pancreas)
4. Plasma kallikrein converts high molcular weight kininogen to bradykinin.
5. Tissue kallikrein converts low molecular weight kininogen to kallidin.

• The kininogens are liver derived alpha2 globulins

Metabolism of kinins
• 2 types of enzymes metabolise kinins:
1. Aminopeptidases
2. Carboxypeptidases

• Aminopeptidases:
• Converts kallidin to bradykinin

• Carboxypeptidase:
• 2 forms:
1. Kininase I
• Inactivates des Arg9 Bradykinin
2. Kininase II (ACE)
• Inactivates bradykinin

Actions of bradykinin
1. Cardiovascular
A. Dilates arterioles and venules
• Not a direct effect. Probably mediated by PGI2 or NO
B. Constricts large arteries and venules
• A direct effect.
• Mediated by des Arg9 Bradykinin which acts on the B1 receptor

2. Neural
• Stimulates sensory nerve endings, eliciting pain (similar to substance P)

3. Others
A. Constriction of smooth muscle
B. In uterus, airways, gut
C. Secretions in airways and gut.

Inflammation is a process which does not involve a single chemical mediator. It involves heaps (e.g. prostaglandins,
leukotrienes, histamine, serotonin, bradykinins) all of which reinforce the actions of each other!

Receptors of bradykinin
• 2 receptors:

Receptor B1 B2
Agonist: Bradykinin des Arg9 Bradykinin
Effects: All effects except vasoconstriction Vasoconstriction
Antagonists: Icatibant Analogues of bradykins
By Duy Thai, 1997 Pharmacology Semester 1 page 4 of 4

Therapeutic drugs
1. Drugs acting on the receptor:
• Icatibant
• Used as a spray
• Rhinitis

2. Drugs acting to inhibit kallikrein

• Aprotinin
• Used to treat angioedema
• Carcinoid syndrome

3. Drugs which increae the action of kinins

• Captopril
• Inhibits ACE (Kininase II) which breaks down bradykinin
• Used to treat hypertension
• Reduces vasoconstriction by:
A. Reducing the amount of angiotensin II (a constrictor)
B. Increasing the amount of bradykinin (a dilator)
• Side effects (as a result of increased kinin levels)
• Cough due to increased bronchial secretion