Angiotensin II

and
Renin Angiotensin System

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 Angiotensin II and the Renin-Angiotensin
System

• The renin-angiotensin system (RAS) has been shown to

reside within several organs and cells, such as heart,
kidney, lung, brain, cardiac myocytes, endothelial cells and
vascular smooth muscle cells.

• It plays a mojor role in the regulation of hemodynamics

and water and electrolyte balance via its circulating
hormone, angiotensin II.

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 Biosynthesis
• The principle step in the biosynthesis of angiotensin II, is the

enzymatic cleavage of angiotensinogen, to give the decapeptide

angiotensin I. This is achieved by the enzyme renin.

• Conversion of angiotensin I to the active octapeptide angiotensin II

is catalyzed mainly by the angiotensin converting enzyme (ACE).

• Degradation of angiotensin II to the inactive heptapeptide

angiotensin III is catalyzed by aminopeptidases.

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 Renin-Angiotensin System
• Angiotensin I, II:
– Angiotensin I is rapidly converted to angiotensin II.

• Angiotensin converting enzyme (ACE):

– Converts angiotensin I to angiotensin II. Nonspecific. Cleaves
dipeptides from many substrates (e.g. bradykinin).

• Aminopeptidases:
– Nonspecific, involved in degradation of angiotensin II and III

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Biosynthesis

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• ACE exists most abundantly in the lung bound to the

endothelial cells of the lung capillaries.

• Renin is the rate limiting step in angiotensin I synthesis.

• Renin is synthesized as preprorenin that is processed to

a prorenin, which is inactive, then to the active renin.

• This occurs in the kidney in specialized cells called the

juxtaglomerular cells.

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 The Juxtaglomerular apparatus

• It is the site of synthesis, storage and release

of renin.
• It is a conjunction of afferent arteiole,
efferent arteriole and distal convoluted
tubule near the glomerulus.

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Juxtaglomerular Apparatus

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A change in fluid pressure in the extracellular region is
sensed by the JUXTAGLOMERULAR CELLS
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 The JUXTAGLOMERULAR apparatus

• This apparatus comprises two types of specialized cells in

the afferent arteriole and the distal tubule.
1. The JUXTAGLOMERULAR (JG) cells

2. The macula densa cells.

• The JUXTAGLOMERULAR apparatus believed to play a

fundamental role in controlling the blood flow to the
nephrons and the GFR.

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 The juxtaglomerular apparatus

1. The juxtaglomerular (JG) cells:

– Their function is to release renin into the circulation via
stimulation of Beta(1)-adrenoceptors.

2. The macula densa cells:

– They respond to changes in the flow rate and composition
of the tubular fluid and are thought to control the release
of renin from the JG cells of the afferent arteriole.

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 Control of renin secretion

• Several factors may stimulate renin relases from

the JG cells including:
• Hypotension
• Hypovolemia

• Increase activity of renal sympathetic nerve (B1

receptor mediated)
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 Angiotensin II receptors
• Two types of ATII receptors have been characterized,
both as G-protein coupled receptors.

1. AT 1 receptors: Exist at postsynaptic sites and mediate

most of the known effects of AT II.

2. AT 2 receptors: Exist mainly in the central nervous

system and adrenal medulla. The function of AT 2
receptors is not exactly known.

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Pharmacological actions of Angiotensin II

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 Cardiovascular effects
• Heart:
– Angiotensin exerts positive inotropic and chronotropic effects,
mainly due to the release of NE from sympathetic nerve
terminals.

• Blood Vessels:
– Angiotensin II produces potent vasoconstrictor and pressor
effects. It I 40 times as potent as NE in causing vasocontriction
and raising blood pressure.

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 Cardiovascular effects
Several mechanisms have been suggested to explain the pressor effect of
angiotensin including:
• Stimulation of postsynaptic AT 1 receptors in vascular tissues.
• Releasing catecholamines from adrenal medulla therefore facilitate
sympathetic transmission.
• Inhibition of neuronal uptake of NE
• Stimulation of central sympathetic tone
• Release of aldosterone from adrenal cortex, which increase tubular
reabsorption of sodium

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 Other effects

2. Smooth muscle:
– Angiotensin II contracts smooth muscle of the gastrointestinal

tract, bronchi and urinary bladder.

3. Central nervous system

– Control of thirst (stimulation of drinking) and appetite.

– Stimulation of central sympathetic tone, leading to increase in

blood pressure.

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 Inhibitors of renin-angiotensin system

• The renin-angiotensin system (RAS) is important in the

pathogenesis of heart failure and some kinds of hypertension.

• RAS can be influenced by drugs at four different points:

– Renin release

– Renin activity

– Angiotensin in converting enzyme

– Angiotensin receptors

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 1. Inhibitors of renin release
• Renin is released from the JG cells in response to 1-

adrenoceptor stimulation

• Blockade of these receptors (by -blockers such as

propranolol) reduce renin release from the JG cells

• Drugs that reduce renal sympathetic activity and NE relase

would also reduce renin release, e.g. clonidine and -

methyldopa that act centrally to decrease sympathetic activity

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 2. Inhibitors of renin activity

• These drugs reduce plasma renin activity but

they cause small decreases in blood
pressures
• Examples:
– Enalkiren
– Remikiren
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 Angiotensin-converting enzyme inhibitors
(ACE inhibitos)
• Examples
– Captopril

– Enalapril

– Lisinopril

– Quinapril

• These drugs are used clinically in the management of hypertension.

• Because angiotensin converting enzyme (also called kininase II) is responsible

for the degradation of bradykinin, the use of ACE inhibitors would result in the

accumulation of bradykinin.

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 Adverse effects of ACE inhibitors
• Cough

– Of particular interest in the adverse event profile of all ACE

inhibitors is the occurrence of a dry, nonproductive cough,
irritating enough in some to warrant discontinuation of
therapy

• The mechanism of cough development may be related to the

accumulation of bradykinin which is degraded by ACE.

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 Adverse effects of ACE inhibitors

• Angioedema
– Angioedema is the development of edematous
and urticarial areas on the skin, mucous
membranes of subcutaneous tissue.
– It has rare (<1%) but dangerous association with
ACE inhibitor therapy

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 Adverse effects of ACE inhibitors

• Pregnancy
– ACE inhibitors have demonstrated risk to the fetus
in both animal and human studies.

• Renal Impairment
– In some clinical situations of compromised
kidneys, they may actually impair renal function.

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 AT1- receptor antagonists

• Saralasin a peptide analogue of ATII, is a

competitive inhibitor of the vasoconstrictor
effect of AT.
• Because of its short half-life (few minutes) and
the fact that is a partial agonist and must be
given parenterally., it is no longer used clinically.

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 AT-Receptor Antagonists
• Examples
– Losartan, Valsartan, Candesartan

• Non-peptide competitive inhibitors of AT1 receptors.

• Block ability of angiotensins II to stimautlate pressor
and cell proliferative effects.
1. Antihypertensive effects.
2. Lack of “bradykinin” effects

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 Thank You

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