What are the major functions of the renin-angiotensin system? 

Maintain blood pressure, salt and H2O balance 

What are some of the other functions of the renin-angiotensin system? 

Has a role in vasoconstriction of vessels and a role in inflammation 

Fill in the blanks 

The renin-angiotensin system (RAS) is composed of ______ and _____ system. 

The renin-angiotensin system (RAS) is composed of systemic and local tissue system.

True or False

The RAS is involved in only the short term regulation of blood pressure. 

FALSE

- RAS is involved in both short and long term regulation of blood pressure.

What is the only precursor protein for the family of angiotensin peptides? 

Angiotensinogen 

True or False

Angiotensinogen is the rate-limiting factor in the activity of the systemic renin angiotensin system. 

TRUE

Where is angiotensinogen primary synthesized? 

Primarily from the hepatocytes (liver) for the systemic dervied RAS. 

Where else is the pro-hormone angiotensinogen also synthesized? 

This pro-hormone is also synthesized in the CNS, heart, vasculature, kidney, and adipocyte (fat cell). 

True or False?

Pre-pro-angiotensinogen is processed then stored. 

FALSE

Pre-pro-angiotensinogen is processed and constitutively secreted - not stored. 

Angiotensinogen is regulated by other ____ components. 

Regulated by other endocrine components.

In adipose tissue, angiotensinogen mRNA is upregulated by ______. 

In adipose tissue angiotensinogen mRNA is upregulated by INSULIN.

In the hepatocyte angiotensinogen mRNA is upregulated by ________. 

In the hepatocyte angiotensinogen mRNA is upregulated by ESTROGEN.  

Ex. Birth control pills ^ BP b/c estrogen

Angiotensinogen is cleaved by what enzyme to form the N-terminal decapeptide Ang I - which occurs in the circulation?

Angiotensinogen is cleaved by the enzyme RENIN to form the N-terminal decapeptide Ang I by renin which occurs in the circulation?

Glucocorticoids, estrogen, thyroid hormone, insulin and selected cytokines exert what type of control via specific regulatory DNA sequences of the angiotensinogen gene? 

Synthesis can be stimulated by inflammation and _________. 

Synthesis can be stimulated by inflammation and Angiotensin II.

Ang II may exert a positive feedback regulation via an ______ receptor (to make more angiotensinogen). 

Ang II may exert a positive feedback regulation via an AT1 receptor (to make more angiotensinogen).

What are the two lines of investigation that suggest that angiotensinogen contributes to the hypertensive phenotype? 

1) knockout studies in animals

2) polymorphisms within the angiotensinogen gene have been genetically linked with familial hypertension 

Angiotensinogen is the protein from which angiotensins are formed by _______ cleavage reactions. 

Angiotensinogen is the protein from which angiotensins are formed by proteolytic cleavage reactions.

Choose A or B

Angiotensinogen synthesis is under a) simple control?

                                                b) complex control?
 

B) angiotensinogen synthesis is under complex control.

True or False

Angiotensinogen levels in the plasma affect BP 

TRUE 

RAS - RENIN

is a highly substrate and species specific _______ protease enzyme. 

RAS - RENIN

is a highly substrate and species specific aspartyl protease enzyme.

14aa Angiotensinogen--renin-->10aa angiotenin I--ACE-->8aa angiotensin II 

Juxtaglomerular (JG) cells 

What is the initial step in synthesis of RAS - RENIN? 

The formation of the pre-pro-renin by the renin mRNA 

Describe the steps in the synthesis of RAS RENIN

in order:

What is the step after the formation of the pre-pro-renin by the renin mRNA? 

 23 aa "pre" sequence is cleaved, leaving pro-renin that is deposited into granules

the 43 aa pro sequence is cleaved to the active 40,000 Dalton renin molecule  - this occurs in the golgi 

The cleavage and activation of renin is mediated by the enzyme ______

hint: found in the afferent arterioles

The cleavage and activation of renin is mediated by the enzyme CATHEPSIN B.

Renin storage granules migrate to the cellular surface where they release the active enzyme through what process? 

Renin storage granules migrate to the cellular surface where they release the active enzyme through EXOCYTOSIS into the blood (vascular lumen)

Secretion from the JG cells is controlled predominately by what three pathways? 

Macula densa pathway (local w/in the kidney)

Intrarenal barorreceptor pathway (local)

Beta-adrenergic receptor pathway (nervous system) 

The macula densa monitors ____ levels 

Na+ 

Low sodium level is a signal that ____ renin release 

stimulates 

Substances implicated in the feedback singal are ___ and ___ enzyme. 

PGE2 and Cox 2 

Dietary sodium restriction results in an upregulation of the inducible _____ expression. 

Cox 2 

Adenosine is a substance that _____ renin release. 

inhibits 

The renal baroreceptor is an interrenal vascular receptor in the afferent arteriole that _____ renin secretion in response to _____ renal perfusion pressure and attentuates renin secretion as renal perfusion is elevated. 

- stimulates renin secretion

- in response to reduced renal perfusion pressure

What is the most powerful regulator of renin release? 

BP 

The third mechanism regulating renin secretion is __________

beta-adrenergic receptor pathway (nervous system input). 

Direct stimulation of the sympathetic nerves will _______ renin release. 

increase renin release

The beta adrenergic receptor pathway is an acute pathway by which _____ activation of the RAS is provoked by stimuli such as stress and posture 

rapid

The short loop negative feedback sys involves

_____ in renin secretion which result in a ____ in Ang II 

increase in renin

increase in Ang II

Ang II in turn stimulates the _____ on the JC cells to _____ renin release 

AT1R on the JC cells

Inhibit renin release

Long loop negative feedback system

- Ang II increase ___ by AT1R and the increase ____ renin release via _________ 

1) BP

2) inhibits 

3) baroreceptor mechanism 

The primary second messenger is cAMP (for beta-adrenergic and PGE) is

stimulatory or inhibitory? 

Stimulatory 

cGMP is ________ second messenger

an inhibitory 

Renin release is inhibited by an increase in the intracellular _____ 

Ca2+ 

Factors that stimulate cGMP - such as ANP, _________ renin release

inhibits 

- loop diuretics (block NaCl reabsorption)

- NSAIDS inhibit PG

- ACE inhibitors and AT1R blockers interrupt feedback systems

 - B-adrenergic blockers and central acting sympatholytic drugs

Which of the following stimulate renin release?

- loop diuretics

- NSAIDS 

- ACE inhibitors and AT1R blockers

-B-Adrenergic Blockers and central acting sympatholytic drugs 

Stimulate:

- loop diuretics

- ace inhibitors

Decrease:

- NSAIDS

- B-adrenergic blockers 

cAMP (increase/decrease) renin release

cGMP, increases in intracellular calcium - will (increase/decrease) renin release. 

cAMP - increase

cGMP - decrease 

1) plasma

2) extoenzyme

3) endothelial

4) epithelial 

bradykinin 

inhibiting ACE would leave bradykinin active, which vasodialate - causing BP to drop 

Vessels in what parts of the body are rich in ACE? 

Lung, retina, and brain 

Generally, which cells have a higher concentration of ACE?

epithelial cells or endothelial cells? 

epithelial cells 

Chymase enzyme (angiotensin convertase) - found in the heart 

How many inhibitory binding sites per molecule does an endothelial ACE contain? 

Two 

Homozygous individuals for the insertion polymorphism (ii) have _____ levels of ACE in plasma than those who are DD 

LOWER 

1) higher

2) ischemic 

Double 

1) bradykinin

2) Ang I

3) Ang II 

substrate specificity 

ACE 2 catalyzes the formation of a vasodilator molecule ______ from both Ang I and Ang II 

Ang I-7 

ACE 2 may function as an _______ of Ang II action 

antagonist 

Ang II have two specific receptors at ____ and ____ 

AT1 and AT2 

How does AT1R (359aa) respond to the following hormones and cytokines?

- glucocorticoids

- insulin

- mineralcorticoids

- estrogens 

1) glucocorticoids - general increase in receptor #s

2) increase

3) generally a decrease

4) generally a decrease 

opposition 

It may be a result of an incomplete block of the enzyme, increase in Ang I may exceed the inhibitory capacity of ACE I, or there is another route for ANG II formation 

In addition to lowering Ang II, how else can ACE I provide cardiovascular protection? 

Ace inhibition blocks degradation of Ang I-7, which can inhibit Ang II action and ACE inhibition increases bradykinin which can act as a vasodialator. 

wound healing 

There is a strong association of pancreatic function (dysfunction) with _____, ___, and ____. 

1) obesity

2) hypertension

3) diabetes 

Ang II can enhance peripheral noradrenergic neurotransmission by  _____, ______, _____.

1) augmenting NE release

 2) inhibiting uptake of NE

3) Enhancing vascular response to NE 

Ang II can increase ______ outflow, attenuate baroreceptor-mediated reduction in sympathetic discharge, thus ______ and have a _____ effect

also enhances release of ____ 

1) sympathetic

2) increasing arterial pressure

3) dipsogenic (increase h2o intake)

4) ADH 

Ang II stimulates release of hormones from the adrenal gland

- ______ from the medulla

- _____ from the cortex 

1) catecholamines

2) aldosterone 

Pathological alterations in CV structures may involve _____ and/or _____ 

hypertrophy

---

remodeling 

There is (no/strong) evidence for association between reduced fibrinolytic activity and ischemic clinical effects is mediated by the RAS

Strong 

Ang II may act as a cytokine - it can participate in the recruitment of cells where ______ respond to Ang II 

monocytes 

RAS is involved in _______ effects, ________ processes, and healing processes. 

1) vascular

2) exudation 

Aldosterone is produced in the ________ of the adrenal cortex 

zona glomerulosa 

The major function of this mineralocorticoid (steroid) is to act on renal and other epithelia to enhance _______ reabsorption and increase the exretion of ______ and ______.

1) sodium (Na+)

2) Potassium (K+)

3) hydrogen ions (H+) 

The ACE inhibitor has other effects other than just BP reduction 

What are some of the effects of ACE I?

1) reduce _____ hypertrophy 

1) cardiac 

ACE I - effects

2) decrease _____ and in turn ______

- plasmin levels are increased and would _______ 

2) Ang II

- PAI-1

- breakdown clots 

ACE I effects

3) (increase/reduce) platelet action 

3) reduce 

ACE I - effects

4) (increase/decrease) in bradykinin levels 

4) increase 

ACE I - effects

5) (increase/decrease) level of Ang (1-7) 

ACE I - effects

6) pressure (increased/decreased) - ____ load on heart 

6) decrease - less 

Aliskiren 

Activation of the pro-renin receptor also triggers a series of intracellular events, including:

1) activation of the synthesis of _________ activator inhibitor-1

2) activation of _______ extracelluar components such as _____ and collagen

3) increases in the level of ______ suggests renin may contribute to hypertrophy and fibrosis 

1) plasminogen

2) fibrotic - fibronectin

3) TGFb (cytokine agent involved in fibrotic process) 

34% 

Labile

BP is characterized by its _____ and _____ 

Malignant hypertension

80-90%, if untreated, die within ___ years

Common symptom - ______ swelling of the optical disk

Most deaths associated with ____ damage 

1) one

2) papilledema

3) target organ 

Kinins relase ________ and ___

and have act as a vaso_______  

1) EDRF - PG

2) dialator

Where is the source of these agents (local hormone factors)?

1) volume

2) dialator 

Digitalis-like factor, natriuretic factor/oubain-like factor's effect on blood pressure is to _______ intracelluar Na an Ca while _______ NE uptake.

also, enhanced _______ 

1) increases

2) reduce

3) vasoconstriction 

Kidney

a few mmHg pressure change - can get a ____% change in urinary output if system is operating normally 

5-10% of cases of hypertension are ______ (can identify he causes and likely a result of another disease process)

evidence for NaCl includes:

population studies

sodium ____

sodium restriction

animal studies

pathology 

BP increases with age in industrialized countries...

incidence for people over 65 (___%)

under 34 (3%) 

Age

sympathetic nervous system:

___receptors are gradually _____ - reduced sinsitivity when age 

baro-

"reset" 

True or False

There is no single cause for essential hypertension 

Secondary hypertension

What is the renin response in the two kindey, one clip model? 

An increase in the volume to do increased renin due to shut off of renin release by volme increase

Initially elevated - then the excess volume and sodium and pressure shuts down renin release 

Captopril test

oral captopril will _____ aldo and ang II in normal paients so that the ratio of aldo/renin will go down

is this the case in patients with Conn's syndrome? 

decrease

---

No, ratio will not fall in Conn's

CO = elevated

TPR = elevated 

Glucocorticoids can:

1) enhance/decrease vascular reactivity to catecholmines

2) _____ catecholamine uptake

3) increase/decrease synthesis of angiostensinogen

4)increase/decrease AT1 receptors 

1) enhance

2) inhibit

3) increase 

4)increase 

1) volume may not increase, CO is similar to normotensive controls

2) TPR increases

3) responsiveness to Ang II caecholamines, ADH is elevated

4) diurnal BP rhythms are reversed 

The endocrine theory for preeclampsia states that the levels of ET1, deoxycorticosterone, natriuretic factor, insulin resistance, AT1 receptors and EDRF INCREASE

true or false? 

False...

EDRF, prostacyclin, vitamin E all decrease 

True or false?

ACE inhibitors is particularly effective as treatment in the 2nd and 3rd trimesters. 

False

Don't treat with ACE inhibitors, especially in 2nd and 3rd trimester 

When systolic BP > 150 mmHg, the risk of atherosclerosis is:

a) halved 

b) doubled

c) tripled

d) quadrupled 

1) injury to intima and endothelium

2) sequence of repair leads to atheroma

3) platelet deposition, smooth muscle proliferation

4) complicated with elevated lipids 

1) angina

2) myocardial infarction

3) Peripheral cascular disease (aneurysm) 

When systolic pressure is > 160 mmHg, risk of stroke is

a) halved

b) doubled

c) tripled

d) quadrupled 

d) quadrupled 

The eye 

heart failure results in ________

hint: back flow into heart and other organs

Preload is the loading condition of the heart at the (beginning/end) of the diastole

and it is determined by the _______ volume 

end

---

end-diastolic 

True or false

- diastolic dysfunction symptoms never develop during exercise because the higher the heart rate - the lower the filling time. 

False

the higher the heart rate - the lower the filing time - so symptoms WILL develop during exercise