Renin angiotensin system

Question 1

renin-angiotensin-aldosterone system

Answer 1

liver makes angiotensinogen. kidney makes renin

Renin converts angiotensinogen to angiotensin 1

Ang 1–> ang 2 via ace (brady kinin, substance P, enkephalins)
ang 1–> ang 2 via non ace

angiotensin 2 activates angiotensin 2 receptors which cause aldosterone secretion, vasoconstriction and sympathetic activation

causes blood pressure regulation

Question 2

anatomy of juxtaglomerular apparatus

Answer 2

juxtaglomerular cell- modified smooth muscle cell found in the media of afferent arteriole. contain renin granules

macula densa- specialized epithelial cells found at point where distal tubule comes in contact with afferent arteriole

sympathetic nerves- found in media or afferent arteriole

Question 3

renin

Answer 3

the major enzyme that determines the rate of Angiotensin 2 production. it is synthesized, stored and secreted by the granular juxtaglomerular cells located in the walls of the afferent arterioles

An acid protease that splits leucine-leucine bond of angiotensinogen giving angiotensin I

produced in JG cells of kidney

inhibited by aliskiren

Question 4

angiotensinogen/renin substrate

Answer 4

angiotensinogen is the substrate for renin and is an abundant globular glycoprotein

inflammation, insulin, E, glucocorticoids, Thyroid and angiotensin 2 stimulate angiotensinogen synthesis

During pregnancy, plasma levels of angiotensinogen increase several fold

An alpha2 globulin, synthesized by liver, amino-terminal sequence contains angiotensin 1

Question 5

converting enzyme (ACE)

Answer 5

an ectoenzyme and glycoprotein, and has 2 homologous domains, each with a catalytic site and a Zn-binding region

The very rapid conversion of Ang 1 to Ang 2 that occurs in vivo.

Membrane bound ACE present on the luminal surface of endothelial cells

Removes C-terminal of Ang 1

found in vascular endothelium, lung, kidney and plasma

Inactivates bradykinin

Inhibited by Captopril, Enalapril, Lisinopril

Question 6

angiotensin 1

Answer 6

angtiotensin 1 is less than 1% as potent as angiotensin 2 on smooth muscle, the heart, and the adrenal cortex
biologically inactive

Question 7

angiotensin 2

Answer 7

biologically active, t.5= 4 min, octapeptide

Question 8

angiotensinases

Answer 8

nonspecific aminopeptidases and carboxypeptidases, inactivate angiotensin 1 and 2

Question 9

aldosterone

Answer 9

synthesized by zona glomerulosa cells of the adrenal cortex

synthesis stimulated by potassium, ACTH, and angiotensin 2

mineralcorticoid that acts on distal tubule and collecting duct to enhance Na REAB and K excretion

action is inhibited by spironolactone and eplerenone

Question 10

control of renin release

Answer 10

rate limiting step in activation of renin angiotensin system

Question 11

intrarenal baroreceptor

Answer 11

• increases and decreases in bp or renal perfusion pressure in the pre glomerular vessels inhibit and stimulate renin release respectively
• release of renal prostaglandins and biomechanical coupling via stretch activated ion channels mediate in part the intra renal baroreceptor pathway
• senses changes in wall tension of afferent arteriole
• wall tension is inversely related to renin release (increase in vascular pressure/afferent arteriolar vasoconstriction will increase wall tension and decrease renin release) (decrease in vascular pressure/afferent arteriolar vasodilation –> decrease in wall tension and decrease renin release)

Question 12

macula densa

Answer 12

lies adjacent to juxtaglomerular cells and is composed of specialized columnar epithelial cells in the cortical thick ascending limb that passes between the glomerular afferent and efferent arterioles)

A change in NaCl REAB by macula densa –> juxtaglomerular cells to modify renin release

1. senses changes in Na load presented to the macula densa segment of distal tubule
2. Na load is inversely related to renin release (increase salt intake or mineralocorticoids will increase Na load and decrease renin release). (decrease Na intake, Na deprivation, diuretic therapy or decrease GFR, causes decrease in Na load and increase in renin release)

Question 13

Renal sympathetic nervous system

Answer 13

the B adrenergic receptor pathway release of norepinephrine from post ganglionic sympathetic nerves–> activation of B1 receptors on juxtaglomerular cells to enhance renin secretion

1. mediated by B 1 adrenergic receptors on JG cells
2. renin release is increased by direct or indirect activation of renal sympathetic nerves or beta-adrenergic agonist
3. renin release is decreased by reduction in sympathetic nerve activity or beta-adrenergic blockers such as propranolol or metoprolol

Question 14

angiotensin 2

Answer 14

1. angiotensin 2 causes feedback inhibition
2. suppresses renin release by direct action on JG cells
3. At1 receptor antagonists and converting enzyme inhibitor stimulate renin release by blocking this feedback inhibiotn

Question 15

MOA of angiotensin 2

Answer 15

angiotensin 2 couples to GPCR designated AT1 and AT2

AT1 mediates major biological effects of angiotensin 2

Specific angiotensin receptors (AT1 and AT2) blocked by losartan

mediated by calcium
AT1-> Gq -> PLC -> IP3 -> Ca

Question 16

vascular smooth muscle

Answer 16

angiotensin 2 activates AT1 receptors to constric arterioles (lesser extent venules)

• Vascular beds have varying responses to angiotensin 2.
• direct vasoconstriction is strongest in the kidneys and splanchnic vascular beds
• Angiotensin 2-induced vasoconstriction is much less in brain lung and skeletal muscle
• high amounts of angiotensin 2 decrease cerebral and coronary blood flow

Question 17

At 1 receptor mediated

Answer 17

1. arteriolar vasoconstrictor-increase in blood pressure
2. hypertrophy- increase in wall to lumen ratio (increase in migration, proliferation, and hypertophy). increased extracellular matrix proteins such as collagen

Question 18

At2 receptor mediated

Answer 18

Endothelium-dependent vasodilation- NO mediated
Inhibition of proliferation of smooth muscle
Promotes apoptosis

Question 19

Renal hemodynamics

Answer 19

angiotensin 2 activates AT1 receptors on renal vascular smooth muscle to reduce renal blood flow

Angiotensin 2 influences GFR by several mechanism: afferent arteriolar constriction reduces intraglomerular pressure and tends to reduce GFR
mesangial cell contraction decreases the glomerular capillary surface area available for filtration and tends to decrease GFR
efferent arteriolar constriction increases GFR

overall GFR is slightly reduced by Angiotensin 2

Question 20

adrenal cortex- angiotensin 2

Answer 20

angiotensin 2 stimulates the zona glomerulosa of the adrenal cortex to increase aldosterone synthesis and secretion
Aldosterone stimulation is elicided at ANg 2 levels have little or no acute effect effect on BP

1. stimulates aldosterone biosynthesis and secretion via At1 receptor
2. promotes Na REAB indirectly
3. Effects of aldosterone are blocked by spironolactone or eplerenone

Question 21

angiotensin 2 and CNS

Answer 21

promotes thirst-dipsogenic
promotes ADH release
Promotes positive water balance

Question 22

Angiotensin 2 and Sympathetic NS

Answer 22

1. sympathetic neuron- facilitates Ne release, inhibits Ne reuptake
2. adrenal medulla promotes Epi secretion

Question 23

angiotensin and heart

Answer 23

hypertrophy of cardia myocytes

increase in extracellular matrix production by fibroblasts

Question 24

mo actions of aldosterone

Answer 24

specific mineral cort receptor agonist
activates expression of target genes involved in Na REAB and K secretion
inhibited by mineral cort receptor andtagonists spironolactone and eplerenone

Question 25

aldosterone and kidney

Answer 25

acts on principle cells of collecting ducts

Na REAB and K secteion

Question 26

aldosterone and heart

Answer 26

pathological alteration involving cardiac hypertrophy and remodeling increase morbidity and mortality

angiotensin 2: stimulates vascular smooth muscle cell migration, proliferation, and hypertrophy. increases vascular smooth muscle cell extracellular matrix production, causes cardiac myocyte hypertrophy, increases cardiac fibroblast extracellular matrix production

these effects of angiotensin are mediated by acting directly on cells to induce the expression of specific proto-oncogenes, that alter the expression of growth factors.
Angiotensin 2 also alters extracellular matrix formation and degredation indirectly by increasing aldosteron

cardiac fibrosis- both ventricles
Left ventricular hypertrophy

Question 27

congestive heart failure angiotensin 2

Answer 27

a vasoconstrictor- increases afterload

activates SNS, arrythmogenic, promotes mycardial hypertrophy and apoptosis, releases aldosterone

Question 28

aldosterone CHF

Answer 28

promotes NA and water retention- increases pre load

cardiac fibrosis, left ventricular hypertrophy

Question 29

angiotensin 2 receptor antagonists

Answer 29

block AT1 receptors
losarton
competitve angiotensin receptor antagonist- selective for AT1 receptor subtype. angiotensin acts on AT2 receptors unopposed

even though its competitive inhibition, blocker is insurmountable

orally active- treatment of essential HTN. effect related to pretreatment plasma renin activity

reduces BP without increasing heart rate. (contraindicated in pt with volume depletion or on diuretics, hypotension possible)

renal function may decrease in pt with congestive heart failure or renal artery stenosis.

Question 30

use of losarton

Answer 30

improves heart failure- decreases blood pressure (afterload), reduces left ventricular filling pressure. Decreases aldosterone reducing Na retention, cardiac fbrosis, cardiat hypertrophy, decreases preload. Improves survival in HF due to systolic dysfunction.

contX in pregnancy. Plasma concentration increases in pts with reduced liver function.

SE-dizziness, cough, angioedema, hyperkalemia

does not alter lipid profile

Question 31

ACE inhibitors

Answer 31

inhibit angiotensin 2 formation and bradykinin degredation

sulfhydryl containing ACE inhibitor: Captopril
dicarboxyl containing ACE inhibitor: Enalapril and lisinorpril

orally active agents for treatment of HTN (essential)

reduce BP without increasing Heart rate. (diuretics enhance their action)

enalapril and lisinopril are prodrugs (long duration of action) (pril–> prilate)

lowers aldosterone release so hyperkalemia may occur

SE: rash, proteinuria, neutropenia, Captopril. Cough and angioedema

Question 32

comparison of angiotensin AT1 receptor blocker (ARB) to ACE inhibitor

Answer 32

ARBs more effectively block AT1 receptors activation. ACE inhibitors reduce biosynthesis of angiotensin (but there are alternative non Ace angiotensin 2 generating pathways)

AT2 receptor activation occurs with ARB but not ACE inhibition

ACE inhibitors increase renin release

ARBs increase renin and angiotensin 2 levels that can bind to AT2 receptor

ACE increases bradykinin

Question 33

renin inhibitor

Answer 33

antihypertension drug.

Angiotensinogen is the only specific substrate for renin and its conversion to angiotensin 1 is a rate limiting step of the RAS

Question 34

Aliskiren

Answer 34

renin inhibitor. Potent active site, non peptide inhibitor. Specific for renin no inhibition of other aspartic proteases

orally active, long acting (t.5=24hrs, treats HTN w/o HR change, enhanced by diuretic/ACE inhibitor or ARB, decreases Ang 2 plasma and aldosterone concentration

Question 35

aldosterone antagonists

Answer 35

block minerlocorticoid receptor
Spironolactone, eplerenone

competitve aldosterone antagonist at mineralocorticoid, diuretics, orally active, reduce mortality from heart failure (decreases cardiac hypertrophy , fibrosis, Na retention)

used with thiazide or loop diuretic to treat HTN or edema