RAAS lecture Flashcards
Renin-angiotensin system is an important regulator of
blood pressure (short & long term) & hydromineral balance
how many groups of drugs target RAS?
3- at different levels
protein
a macromolecule with large amino acid sequence (>50 AAs)
peptide
a short amino acid sequence (20-30 AAs)
proteolytic enzyme/ protease/ peptidase
an enzyme that cleaves peptide bonds in peptides & proteins
receptors
proteins (usually located on the plasma membrane) to which ligands (hormones, NTs) bind & cause certain effects
what enzyme converts angiotensinogen to angiotensin I?
renin
-rate liming step**
is angiotensinogen active or inactive?
inactive
is angiotensin I active or inactive?
inactive
angiotensinogen
us a glycoprotein synthesized & secreted by liver
renin
an enzyme (protease) synthesized, stores & released into circulation by juxtaglomerular cells of kidney
angiotensin I
is an inactive peptide, precursor of active angiotensin- formed in systemic circulation
what cells produce renin
juxtaglomerular cell
what enzyme converts angiotensin I to angiotensin II?
ACE
angiotensin converting enzyme (ACE)
protease on the membrane of vascular endothelial cells & circulating in blood
- also degrades bradykinin
angiotensin II
main active peptide, formed in systemic circulation, acts through AT1 & AT2 receptors
AT1 receptors is the mediator of
pressor effects
angiotensin (1-7)
some effects are opposite of angiotensin II; mediated through its own receptor (Maz receptor)
- can be formed from both angiotensin I &II
what enzyme converts angiotensin I to angiotensin (1-7)?
NEP (neutral endopeptidase)
what enzyme converts angiotensin II to angiotensin (1-7)?
ACE2
increase release of renin leads to
more angiotensin II & ELEVATED BP!
what are the 3 long-loop pathways that regulate renin release?
- macula densa pathway
- intrarenal baroreceptor pathway
- B-adrenergic receptor pathway
macula densa pathway
decrease NaCl flux across macula densa-> increase renin release
inrarenal baroreceptor pathway
decrease BP in afferent arteriole_> increase renin release
B-adrenergic receptor pathway
activation of B1 receptors (by SNS-NE) on juxtaglomerular cells-> increas renin release
increase circulating angiotenin II leads to
decreased renin release
regulation of renin release
- short- loop negative feedback
2. long-loop negative feedback
short-loop negative feedback
stimulating angiotensin receptors on juxtaglomerular cells-> decrease renin release
long-loop negative feedback
increase circulating angiotensin II->incr. BP-> decr. renin
AT2 receptors
often opposite of AT1
- in vasculature mediate vasodilation
AT1 receptors in vasculature
vasoconstrictors
promotes SM hypertrophy (chronic effect)
AT1 receptors in adrenal cortex
stimulation of synthesis & secretion of aldosterone
AT1 receptors in adrenal medulla
stimulation of epinephrine release
AT1 receptors in kidney
- efferent arteriole vasoconstriction
inhibition of renin release from JG cells - increase Na rebsorption in the proximal tubule
AT1 receptors in heart
stimulation of myocardial hypertrophy & collagen synthesis
AT1 receptors in brain
increased release of vasopressin (ADH), stimulation of thirst & salt appetite, increased central sympathetic outflow
pressor effects of angiotensin I through AT1 receptor
> PR (Vasoconstriction), aldosterone (retention of Na & H2O), Na retention, sympathetic tone, hypertrophy in blood vessels & myocardium (chronic effect)
angiotenin (1-7) effects
vasodilation, increased diuresis, anti-inflammatory
ACE inhibitors MOA
- decr, formation of angiotensin II
- incr. cicrulating bradykinin
- incr. formation of antiotensin (1-7) (indirectly)
also increase renin levels bc of the negative feedback loop is not functional
sensitivity to ACEI is increased in patients with
activated RAS (low salt diet, HF)-> profound effects
in HTN ACEI
- decr. vascular resistance & BP
- incr. compliance of larger arteries
- . slight decrease in GFR
- aldosterone secretion is slightly decreased (risk for hyperkalemia)
- cardiac function is usually UNCHANGED
main therapeutic uses of ACEI
HTN, left ventricular systolic dysfunction, acute MI, prevention of CAD events & stroke, chronic renal failure
how do ACEI cause hyperkalemia?
blocking angiotensin II-> decreased aldosterone which can lead to an increase build up of potassium
main ADE of ACEI
hypotension, cough, hyperkalemia, acute renal failure(in predisposed pts), modest elevation of SCr, in combo w/ NSAIDs-> decr. GFR, teratogenic effect, rash, angioedema, dysgeusia(loss of taste), neutropenia
how do ACEI cause cough?
accumulation of bradykinin, substance P &/or prostaglandins in lungs.
iron supplement may be beneficial
AT1 receptor blockers aka
ARBs
-sartan
ARB result in
- arterial vasodilation & reduction of PR
- reduction of serum aldosterone levels
inhibition of peripheral sympathetic activity - improvement of hemodynamic profile in heart & kidney
- also cause incr. renin (loop feedback in inhibited & incr. angiotensin II in plasma (but binding is prevented)
ACEI vs. ARBs
- ARBs reduce activation of AT1 receptors more efficiently
- ACEI increase renin but NOT angiotensin II while ARBs increase both
- in case of ARBs generated angiotensin II can act on AT2 recptors (often opposite effect of AT1 receptors)
- ACEI may increase angiotensin (1-7) more than ARBs
- ACEI increase levels of bradykinin
main therapeutic uses of ARBs
HTN, HF, stroke prophylaxis, diabetic nephropathy
Main ADE of ARBs
- comparable w/ placebo
- hypotension, esp. in salt-depleted individuals
- less potential for angioedema
- hyperkalemia
- teratogenic potential
renin inhibitor
aliskiren
aliskiren is indicated for
the treatment of HTN as monotherapy & in combo
main ADE of aliskiren (renin inhibitor)
similar to placebo
- HA, fatigue, dizziness, diarrhea, nasopharyngitis, epistazis (nosebleed), hyperkalemia, hyperuricemia, teratogenic
