Renin angiotensin system Flashcards
renin-angiotensin-aldosterone system
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
anatomy of juxtaglomerular apparatus
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
renin
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
angiotensinogen/renin substrate
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
converting enzyme (ACE)
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
angiotensin 1
angtiotensin 1 is less than 1% as potent as angiotensin 2 on smooth muscle, the heart, and the adrenal cortex
biologically inactive
angiotensin 2
biologically active, t.5= 4 min, octapeptide
angiotensinases
nonspecific aminopeptidases and carboxypeptidases, inactivate angiotensin 1 and 2
aldosterone
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
control of renin release
rate limiting step in activation of renin angiotensin system
intrarenal baroreceptor
- 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)
macula densa
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
- senses changes in Na load presented to the macula densa segment of distal tubule
- 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)
Renal sympathetic nervous system
the B adrenergic receptor pathway release of norepinephrine from post ganglionic sympathetic nerves–> activation of B1 receptors on juxtaglomerular cells to enhance renin secretion
- mediated by B 1 adrenergic receptors on JG cells
- renin release is increased by direct or indirect activation of renal sympathetic nerves or beta-adrenergic agonist
- renin release is decreased by reduction in sympathetic nerve activity or beta-adrenergic blockers such as propranolol or metoprolol
angiotensin 2
- angiotensin 2 causes feedback inhibition
- suppresses renin release by direct action on JG cells
- At1 receptor antagonists and converting enzyme inhibitor stimulate renin release by blocking this feedback inhibiotn
MOA of angiotensin 2
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
vascular smooth muscle
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
At 1 receptor mediated
- arteriolar vasoconstrictor-increase in blood pressure
- hypertrophy- increase in wall to lumen ratio (increase in migration, proliferation, and hypertophy). increased extracellular matrix proteins such as collagen
At2 receptor mediated
Endothelium-dependent vasodilation- NO mediated
Inhibition of proliferation of smooth muscle
Promotes apoptosis
Renal hemodynamics
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
adrenal cortex- angiotensin 2
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
- stimulates aldosterone biosynthesis and secretion via At1 receptor
- promotes Na REAB indirectly
- Effects of aldosterone are blocked by spironolactone or eplerenone
angiotensin 2 and CNS
promotes thirst-dipsogenic
promotes ADH release
Promotes positive water balance
Angiotensin 2 and Sympathetic NS
- sympathetic neuron- facilitates Ne release, inhibits Ne reuptake
- adrenal medulla promotes Epi secretion
angiotensin and heart
hypertrophy of cardia myocytes
increase in extracellular matrix production by fibroblasts
mo actions of aldosterone
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
aldosterone and kidney
acts on principle cells of collecting ducts
Na REAB and K secteion
aldosterone and heart
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
congestive heart failure angiotensin 2
a vasoconstrictor- increases afterload
activates SNS, arrythmogenic, promotes mycardial hypertrophy and apoptosis, releases aldosterone
aldosterone CHF
promotes NA and water retention- increases pre load
cardiac fibrosis, left ventricular hypertrophy
angiotensin 2 receptor antagonists
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.
use of losarton
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
ACE inhibitors
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
comparison of angiotensin AT1 receptor blocker (ARB) to ACE inhibitor
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
renin inhibitor
antihypertension drug.
Angiotensinogen is the only specific substrate for renin and its conversion to angiotensin 1 is a rate limiting step of the RAS
Aliskiren
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
aldosterone antagonists
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
