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R
ENIN
-A
NGIOTENSIN
-A
LDOSTERONE
S
 YSTEM
3 families of drugs:angiotensin-converting enzyme (ACE)- ACE inhibitors have roles in treatment of hypertension, heartfailure, and diabeticnephropathy- ACE inhibitors are indicated for myocardial infarction andprevention of cardiovascularevents in patients at riskangiotensin II receptor blockers (ARBs)- indications are limited to hypertension, heart failure, anddiabetic nephropathyselective aldosterone receptor blockers- eplerenone (only one available) is approved only forhypertension
I. P
HYSIOLOGY 
 
OF
R
ENIN
-A
NGIOTENSIN
-A
LDOSTERONE
S
 YSTEM
- plays an important role in regulating blood pressure, blood volume, andfluid and electrolytebalance- appears to mediate certain pathophysiologic changes associated withhypertension, heart failure, andmyocardial infarction- exerts its effects in large part through angiotensin II
A. T
 YPES
 
OF
A
NGIOTENSIN
 
- consists of:angiotensin I – precursor of angiotensin II, has very littlebiologic activityangiotensin II – has very high biologic activityangiotensin III – formed by degradation of angiotensin II, hasmoderate biologic activity- small polypeptides
B. A
CTIONS
 
OF
A
NGIOTENSIN
II
- mediates essentially all of the effects of RAAS- most prominent actions are vasoconstriction and stimulation of aldosterone release- actions serve to raise blood pressure- can act on the heart and blood vessels to alter their morphology
1. Vasoconstriction
– angiotensin II acts directly on vascular smooth muscle(VSM) to cause contraction- vasoconstriction is prominent in arterioles and less so in veins- a result of induced vasoconstriction is raising blood pressure- can cause vasoconstriction indirectly by acting on:
•
sympathetic neurons to promote norepinephrine release
•
adrenal medulla to promote epinephrine release
 
•
central nervous system to increase sympathetic outflow toblood vessels
2. Release of Aldosterone
– angiotensin II acts on the adrenal cortex topromote synthesis and secretionof aldosterone- aldosterone acts on the kidney to cause retention of sodium andexcretion of potassium andhydrogen- aldosterone increases plasma volume, increasing blood pressure- adrenal cortex is highly sensitive to angiotensin II and can bestimulated to releasealdosterone even when angiotensin II levels are too low toinduce vasoconstriction- aldosterone secretion is enhanced when sodium levels are low andwhen potassium levels arehigh
3. Alteration of Cardiac and Vascular Structure
– angiotensin II maycause pathologic structurechanges in the heart and blood vessels- thought to cause both hypertrophy (increased mass of a structure)and remodeling(redistribution of mass within a structure)- in hypertension, may be responsible for increasing the thickness of blood vessel walls- in atherosclerosis, may be responsible for thickening intimalsurface of blood vessels- in heart failure and myocardial infarction, may be responsible forcausing cardiac hypertrophyand fibrosisKnown effects:
•
increased migration, proliferation, and hypertrophy of VSMcells
•
increased production of extracellular matrix by VSM cells
•
hypertrophy of cardiac myocytes
•
increased production of extracellular matrix by cardiacfibroblasts
C. F
ORMATION
 
OF
A
NGIOTENSIN
II
BY 
R
ENIN
 
AND
A
NGIOTENSIN
-C
ONVERTING
E
NZYME
 
- angiotensin II is formed through two sequential reactions:1
st
– catalyzedby rennin2
nd
– catalyzed by ACE
1. Renin
– catalyzes the formation of angiotensin I from angiotensinogen- rate-limiting step in angiotensin II formation- produced by juxtaglomerular cells of the kidney
 
- undergoes controlled release into the bloodstream, convertingangiotensinogen intoangiotensin I
a.
Regulation of Renin Release – factors that regulate renin releaseregulate the rate of angiotensin II formation- regulated by classic negative feedback loop
Renin Release Triggers:
•
release increases in response to decline in bloodpressure, blood volume,plasma sodium content, or renal perfusionpressure
•
reduced renal perfusion pressure (especially importantstimulant) can occur inresponse to:stenosis of the renal arteriesreduced systemic blood pressurereduced plasma volume (brought on bydehydration,hemorrhage, or chronic sodiumdepletion)
•
sympathetic nervous system increase secretion bystimulation of beta
1
adrenergic receptors on juxtaglomerular cells
Renin Suppression Factors:
•
inhibited by elevation of blood pressure, blood volume,and plasma sodium content
2. Angiotensin-Converting Enzyme (Kinase II)
- ACE catalyzes the conversion of angiotensin I (inactive) intoangiotensin II (highly active)- ACE is located on the luminal surface of all blood vessels,vasculature of the lungs beingespecially rich in the enzyme- because ACE is abundant, conversion of angiotensin I intoangiotensin II occursalmost instantaneously- ACE is a relatively nonspecific enzyme that can act on avariety of additionalsubstrates- substrate as angiotensin I = referred to as ACE- enzyme acting on other substrates = different names- substrate as hormone bradykinin = referred to asKinase II
D. R
EGULATION
 
OF
B
LOOD
P
RESSURE
 
BY 
R
ENIN
-A
NGIOTENSIN
-A
LDOSTERONE
S
 YSTEM
 
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