Lecture 32: Vasoactive Peptides and Inhibitors, The Renin Angiotensin Aldosterone Syndrome Flashcards
What is the rate limiting step of the RAAS pathway?
Renin
What causes renin release?
What causes renin release?
What kind of compound is angiotensin?
A protein or polypeptide
What turns off renin activity?
- Angiotensin II binding to its receptors
- angiotensin II floating around blood will turn off renin production
- negative feedback loop with angiotensin II
What are the two receptors for Angiotensin II?
- AT1 subtype
2. AT2 subtype
What are the key characteristics of AT1 subtype?
One of the two subtypes of angiotensin II receptors
Primarily responsible for vasoCONSTRICTION
GPCR (G protein coupled receptor)
Concentrated in the following:
i. vasculature
ii. myocardial tissue
iii. renal tissue
What is Losartan?
An antagonist for AT1 subtype
What is the response of angio II binding to AT1?
- Vasoconstriction
- Aldosterone release
- Cell proliferation
- hypertrophy
- matrix deposition (increase in fibrosis)
What are the characteristics of AT2 subtype?
Uterus and fetus is where it is expressed
Constitutively expressed but can be induced
Not sure what this guy does
What type of angiotensin receptor can be induced in expression?
AT2
What is the response of angio II binding to AT2?
- vasoDILATION
- bradykinin, NO and cGMP release
- antiproliferation
- apoptosis
What is the effect of angio II on CNS?
Angio II can access brain regions lacking blood brain barrier
Results in
i. central pressure response resulting from sympathetic activation
ii. Endocrine: release of ADH and ACTH
iii. Behavioral: increases thirst and sodium appetite
Intake and Retention of fluid
What is the effect of angio II on the sympathetic nervous system?
- increases release and decrease uptake of NE from postganglionic neurons
- enhances the sensitivity of target tissues to NE
- Net effect is vasoconstriction
Angiotensin II is synergistic with NE
What is the effect of angio II on the adrenal medulla? Adrenal cortex?
- Release of catecholamines from chromaffin cells
2. Stimulates synthesis and release of aldosterone
What is angiotensin II’s effect on kidney?
- antidiuresis and antinatriuresis
- reduces glomerular filtration
- inhibits renin release (negative feedback)
How does angiotensin II lead to disease?
- can lead to HTN through vasoconstriction (slide 17)
- angiotensin II also has growth factor like effects on cardiac myocytes/smooth cells leading to
i. cell proliferation/apoptosis (slide 18)
ii. HYPERTROPHY
iii. fibrosis in myocytes - Has a pro inflammatory response in vascular tissue
i. impairs endothelial cell function and induces oxidation
Slide 19
How does angiotensin II initiate atherosclerosis?
- Facilitates LDL oxidation and increases uptake in macrophages = INCREASE of foam cells = fatty deposition
- Induces Endothelial cell to express VCAM-1 for more monocyte adhesion (inflammatory cells)…PRO-INFLAMMATORY
- Induces NFkappaB activation to recruit monocytes
- Induces Smooth muscle cell to increase IL-6 and thus C-reactive protein (CRP) which is a systemic inflammatory marker
How does angio II facilitate LDL oxidation?
- activates NADPH which generates ROS and oxidates LDL
- Induces Lox-1 Receptor expression which leads to uptake of oxidated LDL
- Leads to endothelial dysfunction do to increase of oxidative stress
What is the cycle of angio II and inflammation?
Too much angio II = oxidative stress = cytokine/leukocyte recruitment = Inflammation
Inflammation leads to increase in ACE, Cathepsin G and Chymase production
ACE, Cathespin G and chymase upregulate angio II
What are ways to manipulate the RAA system pharmacologically?
- beta blockers
- renin blocker
- ACE inhibitors
i. captopril
ii. enalapril
iii. Lisinopril
iv. ramipril - ACE Receptor blocker
i. Losartin - Aldosterone Receptor Antagonist
i. Spironolactone
ii. Eplerenone
What is the relationship between beta blockers and RAA system?
Beta blockers (Beta 1 receptor) decrease adrenergic activation which decreases renin synthesis Because adrenergic activation activates renin, blocking the former will decrease the latter
What are the potential limitations with ACE inhibition?
Lacks specificity for the enzyme
Alternate pathways for angiotensin II production
Poor side effect profile
What are the other pathways to forming angiotensin II? Significance?
- t-Pa, Cathepsin G and tonin can convert angiotensinogen to angiotensin II
- CAGE, cathepsin G and chymase can covert angiotensin I and angiotensin II
Alternate pathways more prominent during disease states
So if you are giving ACE inhibitors, it won’t be as helpful due to these alternate pathways
What happens to angio 2 levels in blood after ACEI therapy is used?
Angio II levels increase due to compensatory mechanism
However, decreased angio II lvels are not what is responsible for long-term BP control
Angio II levels actually rise above baseline
However, BP still stays controlled because of upregulation of bradykinin
How do ACE inhibitors regulate blood pressure even though angiotensin II levels recover due to alternate pathways?
Normally, ACE breaks down bradykinin
When ACE is inhibited by ACE inhibitors, bradykinin increases and will then lead to more vasodilation (and less HTN)
ACEinhibitors = more bradykinin = greater vasodilation and drop in BP
What are the adverse effects of bradykinin (of ACE inhibitors)? Significance?
- cough
- angloedema (swelling tongue)
- renal dysfunction
- hypotension
- antigrowth
- antiproliferative
That’s why ACE inhibitors can lead to cough through increase in bradykinin levels
How do you make the ACE inhibitors more specific so that it won’t have the side effects of bradykinin?
Angiotensin II receptor blockers NINJAAAA
At the level of the brain, kidney, adrenal cortex, gut and vascular smooth muscle
What are the limitations with the angiotensin receptor blocker approach?
Loss of vasodilation from loss of bradykinin
However, this problem is overcome by binding only AT1 instead of AT2
By allowing angiotensin II to bind to AT2, then you get vasodilation and BP control
Do ARBs send negative feedback to renin?
No they don’t, they actually maintain/increase renin levels
This is because one of two ways that Renin is downregulated is through the binding of AngioII to the Angio II Receptors
What is PRA?
Plasma renin activity
What does ARB do to the renin, angio I and angio II levels?
Upregulates because it takes away one of the feedback loops
What does ACEI do to renin, angio I and angio II?
Angio II is decreased
ARB and Angio I = increased
What happens if you take out angiotensin II?
You get a shitload more renin because you don’t have negative feedback loop
What is the point of renin inhibitors?
To decrease levels of renin that have increased as a result of no angiotensin II in blood
However, DRI (direct renin inhibition) is NOT effective so more studies still need to be done
What is DRI?
Direct renin inhibition
What is Aliskiren?
A direct renin inhibitor
What are the MoA of spironolactone and eplerenone?
Blocks mineralocorticoid receptors to aldosterone
Therefore promotes natriuresis
What are the examples of ACE inhibitors?
Anything that ends with “-pril”
- Enalapril
- Lisinopril
- Ramipril
- Captopril
What is Enalapril?
An Angiotensin converting enzyme
Blocks ACE specifically
What is Losartan?
A type of Angio 2 receptor blocker (ARB)
Antagonist of AT1
