Where is renin produced and what is unique about this enzyme in the RAAS system?
-Kidney -rate limiting step in RAAS pathway and therefore can be a big drug target
Overview of RAAS enzymes and what they substrates
1. renin released from kidney turns angiotensinogen into angiotensin I 2. ACE turns AG1 into AG2
4 triggers of renin release from the kidney
hypovolemia hyponatremia hypohypotension adrenergic activation
5 organs Angiotensin II affects
1. brain: drink water, eat salt, central pressor (SNS stim.), ADH release, ACTH release, oxytocin release 2. kidney: inhibits renin release, Na and water retention 3. adrenal cortex: aldosterone secretion 4. gut: fluid absorption 5. vasc. smooth muscle: pressor
RAAS system negative feedback
1. AG2 turns off renin conversion to form AG1 2. Receptor occupancy: optimal receptor occupancy by AT1= reduces AG1 formation
Most potent vasoconstrictor made in vivo
Homeostatic role of AGII in normal condition
-when SAP drops, renin release is increased. In addition to an increase in SNS which further increases renin release. but the renin increases AG2 which vasoconstricts, and releases aldosterone which increases intravascular volume.VasoC and increase Na retention help to restore BP
Major angiotensin II receptor subtypes
AT1: highest distribution of receptors in vascular smooth muscle, kidney, adrenal cortex, CNS, pituitary...this is the major player for us!! remember this one!
AT2: highest distribution in uterus, fetus; can be induced in other tissues by unknown mechanisms
both are GPCRs
Response of AGII binding to AT1 vs AT2
AT1: vasoconstriction, aldosterone release, cell proliferation/hypertrophy/matrix deposition; THIS IS THE BAD GUY RECEPTOR!
AT2: vasodilation, bradykinin/NO/cGMP release, antiproliferation, apoptosis
Which AGII receptor is blocked by all available angiotensin receptor antagonists?
AT1: remember this is the receptor responsible for vasoconstriction, aldosterone release, cell proliferation/hypertrophy/matrix deposition!!
T/F: AT1 receptor really only transduces signals involved in messing up the CV system.
False; part of many complex signaling pathways
Angiotensin II effects on CNS
can gain access to brain regions lacking BBB and may also be produced within the brain
responses include: central pressure from activating SNS, endocrine release of ADH, ACTH, behavioral increase in thirst and Na appetite
RAAS effects on the sympathetic nervous system
increases release and decrease uptake of NE from postganglion neurons
enhances sensitivity of target tissues to NE
net effect= vasoconstriction
RAAS effect on the adrenal medulla
release of catecholamines from chromaffin cells
RAAS system effects on adrenal cortex
stimulates synthesis and release of aldosterone from zona glomerulosa cells
action is augmented by hyponatremia and hyperkalemia
RAAS effects on the kidney
antidiuresis and antinatriuresis
inhibits renin release as a function of negative feedback
Actions and implication of angiotensin II on CVD
1. vasoconstriction= HTN
2. GF-like effects on cardiac myocytes and SMCs= cell proliferation/apoptosis, hypertrophy--precipitating factors to LV dysfunction
3. pro-inflammatory response in vascular tissue= impairs endothelial function and induces oxidation
Give an example for class of the effects of angiotensin II and endothelial dysfunction via oxidation
1. AGII leads to activation of NAD(P)H oxidase and formation of ROS
2. this leads to oxidation of LDL and LDL-receptors which increase endothelial uptake of LDL
3. leads to damage due to lipid accumulation within cells adn also the formation of plaques in athersclerosis
4. also initiated inflammation in VSMCs and endothelial cells via NFkB activation
Describe the vicious cycle of AGII and atherosclerosis
AG2 begins to cause oxidative stress, LDL uptake, injury, cytokines, and inflammation. Immune cells coming to the area release other enzymes that can create AG2 and further this process
Summarize the effects of AG2 causing increase peripheral resistance (4 ways)
1. direct vasoconstriction
2. enhancement of PNS: increase NE release, decrease NE reuptake, increase vascular sensitivity to NE
3. increase sympathetic disease (CNS)
4. release of catecholamines from adrenal medulla
all of these = rapid pressor response
3 main ways AGII leads to decreased renal function
1. direct effect to increase Na reabsorption in prox tubule
2. release of aldosterone (increase Na reabsorption and K excretion in distal tubule)
3. Alteral renal hemodynamics: direct renal vasoconstriction, enhaved NE transmission in kidney, increase renal sympathetic tone (CNS)
Hemodynamic and non-hemodynamic ways AG2 leads to vascular and cardiac hypertrophy and remodeling
1. non hemo ways: increase expression of proto-oncogenes, increased production of GFs, increase synthesis of ECM
2. hemo ways: increased afterload (cardiac) and increased wall tension (vascular)
5 drug classes that can alter the RAAS system
1. B-blockers: block adreneric activation and renin release
2. renin inhibitors (DRIs)
3. ACE inhibitors
4. Angiotensin II Receptor Blockers (ARBs)
5. Mineralocortoid R antagonists
List 4 ACE inhibitors
Effect of ACE-Is on feedback loop
-because they decrease levels of AG2, this will cause increased levels of renin by relieving suppression of its release and by decreased AT1 receptor occupancy
3 potential limitations with ACE inhibition
1. Alternate pathways for AGII production: bypass pathways leading to ACE escape where chronic administration of ACEIs fails to consistently suppress AngII levels
2. Non-specificity of the enzyme: reason why ACE espace was still experiencing low BP; inhibiting ACE increased bradykinin/NO to generate vasodilation
3. Poor side effect profile: increase bradykinin= cough, angioedema, renal dysfunction, hypotension; also antigrowth and antiproliferative
Pros and Cons to using ARBs
-do not inhibit the destruction of bradykinin, and therefore, do not cause cough, renal dysfunction, and angioedema
-on the other hand, they lack some of the potentially beneficial vasodilatory effectors of bradykinin. Thought that perhaps if AT1 is blocked, AT2 may not bind AngII and cause vasodilation this way.
Effect of ARBs on negative feedback loop of RAAS
-ARB will block receptor occupancy of AT1 which will limit negative feedback, but AngII levels will still be high and can make up for this by blocking renin release.
Bypass pathways exist to create AngII in the presence of ACEIs. Are these bypass pathways more or less active in dysfunctional vessels?
more function: increasingly unhealthy vessel were found to have greater levels of bypass pathway enzymes. This accounted for their consistent levels of AngII after prolonged ACEI.