Exam 1: Pulgar-RAAS

What is the location for the start of RAAS?

kidney

What is the function of angiotensinogen?

substrate for renin; no other function

Renin cleaves ___aa from angiotensinogen to form ______.

2aa; angiotensin I

The pathway of angiotensinogen-->AngI-->AngII-->AT1R causes ____?

vasoconstriction

The pathway of angiotensinogen-->AngI-->Ang(1-7)-->Mas-R causes____?

vasodilation

Where is renin produced____? Where is angiotensinogen produced?

kidney; liver

What are the functions of angiotensin II?

incr. symp. activity; ADH rel to incr water absorp.; vasoconstriction and incr BP; aldosterone secretion which leads to Na reabsorb and K excretion

What is the overall effect of the angiotensin II functions?

sodium ad water reabsorption therefore volume incr, and incr BP; then the perfusion at the JG cells provides feedback inhibition to stop renin release

The actions caused by activtation of AT1R?

vasoconstriction; hyperplasia; hypertrophy; apotopsis; inflammation; collagen deposition; migration

The actions caused by activation of AT2R or MAS-R?

vasodilation; growth inhibition; anti-inflammatory

Do all essential hypertension patients have increased renin release?

No only 20%; another 20% have decreased renin release; 30% is genetic and others are unknown causes

Increased levels of aniotensinogen are associated with___?

essential hypertension bc you will incr renin release

If you have incr level of ACE you will also have _____ and risk of developing____?

renin release: cardiac ischemia, coronary artery disease, left ventricular hypertrophy and hypertension

The ____ is most impt part of kidney and there are estimated to be ____

nephron; 1-1.5million

The macula densa cells located in the ______ detect ______ and "talk" to the _____ ______ located in the______.

DCT; NaCl in the filtrate; JG cells; afferent arterioles

Factors that promote renin release?

amount of NaCl in glomerular filtrate; intrarenal baroreceptors; sympathetic nervous system activity

If the MD cells detect high Na what is the results of the communication with the JG cells?

high Na cause the MD cells to release adenosine and this tells JG cells to decrease renin release

If the MD cells detect low NaCal what is the results of the communication with the JG cells?

low NaCl cause the MD cells to release prostagladins and this tells JG cells to release renin

What is the special transporter in the MD cells?

Na/K/2Cl symporter

If Na is low how does the MD cell react?

the low Na upregulates nNOS-->NO--COX2 to incr PG production which travels to the JG cells and binds to the PGRs receptor; this is a Gs receptor and uses AC to gen cAMP to then stim renin release

If Na is high how does the MD cell react?

the high Na inhibits nNOS-->NO--COX2 and the Na/K ATPase pumps the Na out of the MD cells and depletes the ATP. This depletion incr ADO levels and ADO fuses with the A1R on the JG cells which is a Gi receptor and inhibits cAMP to then decr renin release

How can ATP alter renin release in a different way?

ATP efflux can cause binding to the P2Y-R on the JG cells and activate Gq receptors and incr Ca rel which decr renin rel

How can AngII act in a feedback mechanism?

Circulating AngII can bind to AT1-R a Gq type nd inhibit renin release

What role to barorecptors play in renin release?

low pressure is detected in the barorecptors in the afferent arterioles stimulate renin release

How can the sympathetic n.s. stimulate renin release?

The renal nerve innervates the JG cells and when stimulate by sympathetic pathways NE binds to the B1-R on JG cells to cause renin release

What other way does AngII decrease renin release (besides the activation of AT1-R on JG cells)?

the vasoconstriction by AngII (angio..-->Ang1--AngII--ATi-R_ on vasculature increase systemic BP and decr renin release by either: decr sympathetic tone in JG cells; incr pressure in afferent arterioles so baroreceptors are not activated; decr Na reabsorption in PCT

What is a consequence of using ACEinh?

ACE inh will decr conversion of AngI-->AngII and therefore decr aldosterone, decr arterial vasoconstriction, inhibit symp activity ie./decr NE, epi,; ACE inh also causes bradykinin to incr and leads to cough and edema

How does AngII incr BP via the AT1-R?

when AngII binds to the AT1-R it produces phosphoinositide hydrolysis in vascular smooth muscle cells to cause contraction and increased PVR

How does the AT2-R affect the RAAS system? and why is this important

role in embryological development and regulates apoptosis, decre cell proliferation and vasodiilation; drugs not approved for preganancy

Which ACEinh would cause an allergy and why?

Captopril bc it contains sulfur

Which ACEinh contains phosphorus?

Fosinopril

All the other "prils" contain what function group usually?

dicarboxyl

ACEinh were first discovered in ___?

pit viper venom

All ACE inh are ester prodrugs except?

captopril, lisinopril, enalaprilat

ACEinh are primarily eliminated by the ____?

kidney

ACEinh cause decr BP by ____?

decr PVR without affecting CO or causing baroreceptor reflex increase in symp activity to the heart

What are the main therapeutic uses of ACE inhibitors? and are these similar to ARB uses?

HTN, CHF, diabetic neuropathy, post MI; all of these occur with ARBs also except post MI; ARBs also treat stroke prophylaxis

What are some AE of ACEinh? and are these similar to ARBs?

severe 1st dose hypotenion; actue renal failure; hyperkalemia; dry cough, angioedema, wheezing; all of these are similar with ARBs except for the cough and angioedema

What is a common DDI of ACE inh?

hyperkalemia iwth K sparing diuretics, NSAIDs decr hypotensive effect

How do ARBs decrease lower BP?

they block the AT1-R and since these are widely distributed in vasculature it will have various effects

Which is the most potent ARB?

candesartan

3 multiple choice options

If the AT1-R is block by an ARB what are the physiological results?

decrease vasoconstriction; decre NE release; decr chatecholamines, decr. aldosterone

What is a benefit of ARB?

limit smooth and cardiac muscle hypertrophy seen in HTN and HF patietnts; they do not alter CO like ACEinh; they do not interfere with bradykinin degradation like ACEinh do

Most ARBS are eliminated by___?

renal and hepatitic means

What does the drug Aliskiren do?

it is a renin inhibitor which prevents the conversion of angiotensinogen to AngI

Aliskiren works well with what other class of drugs?

ARBs

What is a AE of Aliskiren?

birth defects

What is a case where adding an ACEinh or ARB to Aliskiren not be beneficial?

diabetic renal failure

What are some DDi with Aliskiren?

atorvastatin and ketoconazole incre the level; irbesartan decr the level

What is different about the aldosterone receptor?

it is an intracellular receptor

What are some mineralocorticoid receptor antagonist that block aldosterone?

spironolactone; eplereone and finereone

Of these which one looks most like a CCB?

finerenone

2 multiple choice options

What is unique about Finerenone?

it looks like a CCB, highly potent and selective for MR(mineralocorticoid receptor); research shows redcution in markers for cardiorenal damage and lowerrisk of hyperkalemia

What is an ARNI drug? and example?

angiotensin receptor neprilyzin inhibitor; Sacubitril/Valsartan (Entresto)

What is Entreto approved for?

chronic HF with reduced ejection fraction

How does Entresto work?

ARB + a neprilysin inhibitor.

Neprilysin is the enzyme responsible for degradation of several beneficial vasodilatory peptides, so blocking them helps cause vasodilation