Duane C. Hombrebueno

Min Gyun Lee

Chapter Overview

Describes the role renin-angiotensin

system plays in regulating the

cardiovascular system

Critical role in the mechanism of

hypertension and congestive heart failure

Development of therapeutic agents that act

on the various enzymes and receptors

associated with the renin-angiotensin

system

Chapter Overview

Renin-angiotensin system influences

normal physiological function

Components of the system such as renin,

angiotensin I and II, and angiotensin-

converting enzyme

Renin-Angiotensin System

and HypertensionRenin-Angiotensin system – is a hormonal

system that plays a central role in the

control of sodium excretion and body fluid

volume. Interacts closely with the

sympathetic nervous system and

aldosterone secretion in the regulation of

blood pressure.

Renin-Angiotensin System

and HypertensionRenin – a kidney extract produced a potent

vasopressor response.

- An aspartyl protease (MW 35,000 –

40,000).

- Primary source is kidney.

- Cleaves the Leu-Val bond from the

aspartic acid end of the angiotensinogen

polypeptide molecule to release the

decapeptide angiotensin I

Renin-Angiotensin System

and HypertensionAngiotensin – hypertensive substance

isolated and identified as decapeptide

- is a glycoprotein (MW 58,000 – 61,000).

- synthesized primarily in the liver and

brought into the circulatory system

Biochemical Conversion

The Cleavage of a dipeptide (His-Leu)

from the carboxyl terminal of angiotensin

converting enzyme to form octapeptide

which is angiotensin II (a potent

vasoconstrictor)

Angiotensin III is formed by removal of

the N-terminal aspartate residue of

angiotensin II a reaction catalyzed by

glutamyl aminopeptidase

Biochemical Conversion

In contrast to angiotensin II, angiotensin

III has a less potent but significant

regulatory effect on sodium excretion by

the renal tubules

This is primarily resulting from the effect

angiotensin III has in stimulating

aldosterone secretion, a potent

mineralcorticoid.

Vasoconstrictive effects

of angiotensin II

Angiotensin II – stimulates the release of

vasopressin from the hypothalamus.

Vasopressin – also known as antidiuretic

hormone (ADH)

- This peptidic hormone is typically

released to conserve water when body is

dehydrated.

Vasoconstrictive effects

of angiotensin II

Endothelin – a 21 amino acid peptide that is produced in the vascular endothelium and plays a role in the regulation of smooth muscle contraction and contributes to blood pressure regulation.

Aldosterone – secreted by adrenal cortex and elicits its effects at various sites. Responsible for the absorption of sodium in the bloodstream

Regulatory action of the

renin-angiotensin system,

- In controlling sodium and potassium

balance and arterial blood pressure is

modified by vasodilators called kinins.

Kallikrein – is activated in plasma by

noxious influences to act on a kinin,

callidin, which is converted to bradykinin

by tissue enzymes.

Regulatory action of the

renin-angiotensin system,

Bradykinin – enhances release of the

prostaglandins PGE2 and PGI2 within

certain tissues to produce a vasodilatory

effect.

- Converted to inactive products by ACE

and other carboxypeptidases.

ACE – a membrane bound enzyme

anchored to the cell membrane through a

single transmembrane domain.

- Zinc containing glycoprotein (MW

130,000)

- A non specific peptidyldipeptide

hydrolase, widely distributed in mamalian

tissues.

- Is a tripeptide with a free carboxylate

group.

Active sites of ACE

Important binding points

- Cationic site to attract a carboxylate ion

- Zinc ion that can polarize a carbonyl

group of an amide function to make it

more susceptible to hydrolysis.

In the active site, there is a nucleophilic

attack of the amide carbonyl by the y-

carbonyl group of a glutamic acid

residue to cause hydrolysis of peptide.

Important role of renin

angiotensin system

Regulating kidney function

Aldosterone release

Electrolyte balance

Blood volume

Renin-Angiotensin system

inhibitors

Captopril – 1-[(2S)-3-mercapto-2-methyl-

1-oxopropionyl]proline (Capoten)

- Blocks the conversion of angiotensin I to

angiotensin II by inhibiting the

converting enzyme.

- Was designed with a carboxyl group on a

proline and a thiol group was introduced

to enhance binding to zinc ion of ACE.

Lisinopril – 1-[N2-[S-1-carboxy-3-phenylpropyl]-

L-lysyl]-L-proline dihydrate (Privinil, Zestril)

- A lysine derivative of enalaprilat, active

metabolite of enalapril.

- Like all ACE inhibitors, it is an active site-

directed inhibitor of the enzyme, with the zinc

ion used in an effective binding interaction at a

stoichiometric ratio of 1:1

- Pharmacological effect are similar to those of

captopril and enalapril.

ACE-Inhibitors ProDrugs

- Available for the treatment of

hypertension following the clinical

effectiveness of enalapril

- These drugs, like the prototypical drug

captopril, are used in the treatment of

mild to moderate hypertension, either

alone or in conjunction with diuretics or

calcium channel blockers

Enalapril Maleate - 1-[N[(S)-1-carboxy-3-

phenylpropyl]-L-alanyl]-L-proline 1-ethyl

ester maleate (Vasotec)

- Is a long-acting ACE inhibitor.

- Is devoid of the side effects of rash and loss

of taste seen with captopril

- The absence of the thiol group in enalapril

maleate may free it from these side effects.

- The half-life is 11 hours.

Benazepril Hydrochloride - (3S)-3-[[(1S)-1-

carbethoxy-3-phenylpropyl]amino]-2,3,4,5-

tetrahydro-2-oxo-1H-1-benzazepine-1-acetic

acid 3-ethylester hydrochloride (Lotensin)

- Metabolized rapidly to the active diacid

benazaprilat.

- No mutagenicity has been found, even

though these drugs cross the placenta.

Quinapril Hydrochloride - (S)-[(S)-N-[(S)21-

carboxy3-phenylpropyl]alanyl]-1,2,3,4-

tetrahydro-3-isoquinolinecarboxylic acid 1-

ethyl ester hydrochloride (Acuretic)

- forms the diacid quinaprilate in the body. It is

more potent than captopril and equipotent to

the active form of enalapril.

Ramipril - (2S, 3aS, 6aS)-1-[(S)-N-[(S)-1-carboxy-3phenylpropyl]alanyl] octahydrocyclopenta[b]-pyrrole-2-carboxylicacid 1-ethyl ester (Altace)

- Is hydrolyzed to ramiprilat, its active diacid form, faster than enalapril is hydrolyzed to its active diacid form.

- Peak serum concentrations from a single oral dose are achieved between 1.5 and 3 hours.

- ramiprilate formed completely suppresses ACE activity for up to 12 hours, with 80% inhibition of the enzyme still observed after 24 hours.

Fosinopril Sodium - (4S)-4-cyclohexyl-1-

[[[(RS)-1-hydroxy-2-methylpropoxy](4-

phenylbutyl) phosphinyl]acetyl]-L-proline

sodium salt (Monopril)

- Phosphorus-containing ACE inhibitor.

- It is inactive but serves as a prodrug, being

completely hydrolyzed by intestinal and liver

enzymes to the active diacid fosinoprilat

Trandolapril - 1-[2-(1-ethoxycarbonyl-3-

phenylpropylamino)propionyl]octahydroindole-

2-carboxylicacid (Mavik)

- an indole-containing ACE inhibitor that is

structurally related to most of the preceding

agents

- Very similar to Enalapril with the primary

difference occurring in the heterocyclic

systems

- must be hydrolyzed to tranolaprilate, which is

the bioactive species

The End