09 Renin-Angiotensin Flashcards
Where is angiotensinogen synthesized?
Liver
Where is Renin synthesized? What is it’s function?
Juxtaglomerular Cells of Kidney
An acid protease that splits leucine-leucine bond of angiotensinogen giving angiotensin I (biologically inactive decapeptide)
Leads to Vasoconstriction/Aldosterone Secretion/Sympathetic Activation
How is Angiotensin II made?
Angiotensin Converting Enzyme (ACE) converts Angiotensin I into Angiotensin II (biologically active octapeptide)
t1/2 = 4 mins
Leads to Vasoconstriction/Aldosterone Secretion/Sympathetic Activation
What is the function of Angiotensin Converting Enzyme (ACE)? Where is it found?
Removes C-Terminal His-Leu dipeptide from angiotensin I producing angiotensin II, the active peptide
Converts Bradykinin, Substance P, and Enkephalins into inactive fragments
Found in vascular endothelium, lung, kidney and plasma
Where are renin granules located?
Juxtaglomerular cell–modified smooth muscle found in the media of afferent arteriole
What are specialized epithelial cells found at point where distal tubule comes in contact with afferent arteriole of kidney?
Macula Densa
Where are sympathetic nerves found in the juxtaglomerular apparatus?
Found in media or afferent arteriole
What is the function of angiotensinases?
Nonspecific aminopeptidases and carboxypeptidases
Inactivate angiotensin I and II
Where is aldosterone synthesized? Why is it synthesized? What is its function?
Synthesized by zona glomerulosa cells of the adrenal cortex
Synthesis stimulated by potassium, ACTH and angiotensin II
Mineralocorticoid acts on distal tubule and collecting duct to enhance sodium reabsorption and potassium excretion
What is the rate limiting step in activation of the renin-angiotensin system?
Control of Renin Release
What is the function of intrarenal baroreceptors?
Sense changes in wall tension of afferent arteriole
Wall tension inversely related to renin release
Ex. ↑ vascular pressure or afferent arteriolar vasoconstriction will ↑ wall tension and ↓ renin release
↓ vascular pressure or afferent arteriolar vasodilation will __ wall tension and __ renin release
↓ vascular pressure or afferent arteriolar vasodilation will ↓ wall tension and ↑ renin release
What is the function of the macula densa?
Senses changes in sodium load (UNaV) presented to the macula densa segment of distal tubule
Sodium load is inversely related to renin release
Ex. ↓ salt intake, sodium deprivation, diuretic therapy or ↓ GFR will ↓ sodium load and ↑ renin release.
↑ salt intake or mineralocorticoids will __ sodium load and __ renin release.
↑ salt intake or mineralocorticoids will ↑ sodium load and ↓ renin release
What is the function of the renal sympathetic nervous system? What mediates its function?
Renin release is increased by direct or indirect activation of renal sympathetic nerves or beta-adrenergic agonists
Mediated by beta1 adrenergic receptors on JG cells
Renin release is ___ by reduction in sympathetic nerve activity
Renin release is decreased by reduction in sympathetic nerve activity
What is the function of Angiotensin II?
Angiotensin II causes feedback inhibition that suppresses renin release by direct action on JG cells
AT1 receptor antagonists and converting enzyme inhibitor stimulate renin release by blocking this feedback inhibition
Which receptor does angiotensin II prefer to bind?
AT1»_space; AT2
AT1 vs AT2 receptor effects
Specific angiotensin receptors, AT1 and AT2
AT1:
- vasoconstriction
- vascular proliferation
- aldosterone secretion
- cardiac myocyte proliferation
- inc sympathetic tone
AT2:
- vasodilation
- antiproliferation
- apoptosis
What is the mechanism of action when AngII binds AT1? AT2?
AT1:
AT1 →Gq→PLC→IP3 →Ca2+→Response
AT2: Unclear
What is the mechanism of action of AT1 on vascular smooth muscle?
Arteriolar vasoconstrictor–inc BP
Hypertrophy– inc in wall to lumen ratio
- inc in migration, proliferation, and hypertrophy
- inc EC matrix proteins like collagen
What is the mechanism of action of AT2 on vascular smooth muscle?
Endothelium-dependent vasodilation – nitric oxide mediated
Inhibition of proliferation of smooth muscle
Promotes apoptosis
What is the effect of AT1 on the sympathetic nervous system?
The sympathetic neuron releases NE that binds post-synaptic alpha1 receptors leading to vasoconstriction
Ang II blocks the NE reuptake into the pre-synaptic terminal, increasing the duration vasoconstriction
At adrenal medulla, promotes Epi secretion
What is the effect of AngII on CNS?
Promotes thirst-dipsogenic
Promotes ADH release and positive water balance
What is the effect of AngII on the heart?
- Hypertrophy of cardiac myocytes
2. Increase in extracellular matrix production by fibroblasts
What is the action of aldosterone on kidney? Heart?
Specific mineralocorticoid receptor agonist
Activates expression of target genes involved in sodium reabsorption and potassium secretion
At kidney:
- acts on principal cells of collecting duct
- sodium reabsorption, potassium secretion
At heart:
- fibrosis of both ventricles
- LV hypertrophy
What is the role of volume and vasoconstriction in hypertension?
High Renin = Lots of Vasoconstriction -> inc TVR -> inc BP
Low Renin = Lots of volume
What is the role of Angiotensin II in Congestive Heart Failure?
Vasoconstrictor – increases afterload
Activates sympathetic nervous system
Arrhythmogenic– increased force and rate of contractions
Promotes myocardial hypertrophy and apoptosis
Releases aldosterone
What is the role of Aldosterone in Congestive Heart Failure?
Promotes Na+ and H2O retention –increases preload
Cardiac Fibrosis
LV Hypertrophy
During CHF, how is perfusion to the vital organs maintained?
Maintain perfusion of vital organs by increasing preload, stimulating contractility, and increasing arterial tone
Renin-Angiotensin System Inhibitors–function, AEs, contraindications
Drugs that inhibit the RAS by different mechanisms
BP lowering related to plasma renin activity
Dec BP with no change in HR
AE: can cause hypotension
Contraindicated in pregnancy– fetal wasting
Losartan
Angiotensin II Receptor Antagonist
selectively block AT1 receptors
Angiotensin II act on AT2 receptors unopposed
Reduce BP without increasing HR
- caution use in patients with volume depletion or on diuretics (additive effect)
Improves heart failure:
- dec BP (afterload)
- dec aldosterone, reducing Na+ retention (dec preload)
Tx:
- Essential Hypertension
Contraindicated in pregnancy
What drug is a selective AT1 receptor blocker, which reduces BP without increasing HR?
Losartan
Captopril, Enalapril, Lisinopril
Angiotensin converting enzyme (ACE) inhibitors – inhibit angiotensin II formation and bradykinin degradation
Reduce BP without increasing HR
- caution use in patients with volume depletion or on diuretics (additive effect)
Improves heart failure:
- dec BP (afterload)
- dec aldosterone reducing Na+ retention (dec preload)
- inc CO
Enalapril and Lisinopril are prodrugs = long duration of action
Lowers aldosterone release so hyperkalemia may occur–reduces diuretic-induced hypokalemia
Tx: Essential Hypertension
Side effects:
Rash, taste disturbance, proteinuria, neutropenia, cough and angioedema may occur.
What drugs are Angiotensin Converting Enzyme Inhibitors?
Captopril, Enalapril, Lisinopril
Which ACE inhibitors are prodrugs? What does this mean for duration?
Enalapril and Lisinopril are prodrugs = long duration of action
What drug reduces diuretic-induced hypokalemia because it lowers aldosterone release?
ACE inhibitors
Captopril, Enalapril, Lisinopril
What drug decreases both afterload, preload, as well as increases cardiac output?
ACE inhibitors
Captopril, Enalapril, Lisinopril
What side effects can occur with ACE inhibitors?
Rash, taste disturbance, proteinuria, neutropenia, cough and angioedema may occur.
When looking to prescribe anti-hypertensive medication to blacks, what works best: ACE inhibitor or diuretic?
Diuretic works best on blacks who are non-responders to ACE inhibitors
All other races have equal effectiveness from both
Which is superior in reducing mortality due to heart failure: ACE inhibitors or vasodilators?
ACE inhibitors
Why are ACE inhibitors contraindicated in patients with renal artery stenosis?
With decreased efferent arteriolar pressure, GFR decreases
There is a compensatory vasoconstriction via AngII which increases efferent arteriolar pressure thereby increasing renal perfusion pressure and GFR
ACE Inhibitors would prevent the compensatory vasoconstriction resulting in decreased renal perfusion pressure and GFR in addition to increased serum creatinine
Aliskiren
Direct Renin Inhibitors Sections
Potent active site, non-peptide inhibitor
Specific for renin; no inhibition of other aspartic proteases
Decreases plasma angiotensin II and aldosterone concentrations
Long acting (t 1⁄2 = 24h) – given once daily
Antihypertensive effect enhanced by diuretic, converting enzyme inhibitor or angiotensin antagonist
Tx: Hypertension (lowers BP with no change in HR–comparable to angiotensin receptor blocker)
Side effects:
- fatigue, headache, GI symptoms
What drug is a direct renin inhibitor?
Aliskiren
How often does Aliskiren need to be taken?
Long acting (t 1⁄2 = 24h) – given once daily
What drugs can be used to inhibit beta1 adrenergic receptors to lower bp related to plasma renin?
Propranolol (beta1 and beta2)
Metoprolol (beta 1)
Drugs that inhibit beta drenergic receptors:
- Cardiac– dec HR
- Renal– dec renin release
What is the effect of aldosterone antagonists on Angiotensin II ability to vasoconstrict?
Does not effect AngII
AngII still results in vasoconstriction
Spironolactone, eplerenone
Competitive aldosterone antagonists at mineralocorticoid receptor
Inhibit the renal (Na and H2O retention) and extra-renal (fibrosis, inflammation, etc.) actions of aldosterone
Uses:
- diuretic
- hypertension
- heart failure
Reduce mortality from heart failure – decreases cardiac hypertrophy, fibrosis, sodium retention
Used with thiazide or loop diuretic to treat hypertension or edema
What drugs inhibit the renal (Na and H2O retention) and extra-renal (fibrosis, inflammation, etc.) actions of aldosterone?
Spironolactone, eplerenone
