RAS, vasopressin, and kinins Flashcards
Angiotensin II interacts with _____ receptors and angiotensin III interacts with ______ receptor
AT1/2
AT1
which receptor produces HTN, stroke, CV events
ACE-AII-AT1
Mas receptor p’way
alternative processing of AI and AII by ACE2 or endopeptidases leads to to the alt peptide Ang 1-7
Mas comprises a counterregulatory, cardioprotective branch of the classical RAS p’way
where is ACE1 present
endothelial vascular cells, luminal side
where is renin released
in kidney, by juxtoglomerular apparatus
4 mechanisms that control renin release
- renal vascular receptors in the afferent arteriole (stretch)
- macula densa receptor (increased release w decreased Na)
- SNS. increased renal nerve activity leads to norepi release leads to beta adrenoreceptors on JG leads to increased renin
- AII, vasopressin, K all inhibit release of renin.
why do pt on ACE inhibitors have high renin/AI levels
no fb inhibition from AII. (ACE2 is insensitive to ACE inhibitors)
what stimulates renin release
- decreased arterial pressure (via renal baroreceptors and systemic baroreceptors)
- dehydration/hemorrhage (barorecptors in atrium, ventricle, and pulm veins response to decreased BV; chemoreceptors in hypothalamus also respond)
- hyponatremia (sensed by macula densa)
how does angiotensin raise BP (4 actions)
- direct vasoconstriction via AT1 receptors presens on smooth muscle (increase Ca) & slow pressor effect independent of this action
- in CNS, increase SNS activity and vasopressin release
- in PNS, stimulation of norepi release from symp neurons
- adrenal medulla: stim release of epi
other CV effects of angiotensin
- increases HR and contractility, but often offset by the baroreflex
- hypertrophy/tissue remodeling by both non hemodynamic and hemodynamic mechanisms. nonhemodynamic mechanisms involve direct actions of these peptides on vascular smooth muscle cell growth
central actions of angiotensin
- stimulates drinking and increases secretion of ACTH and vasopressin (more angio II than III, much more potent)
- ACTH stimulates synthesis/release of aldosterone (actions of AII/AIII equal here)
renal actions of angiotensin
promotes sodium retention by vasoconstriction and increasing prox tubular Na reabsorption, regulates own production by inhibition to renin release
AT1 receptor
G-pro coupled receptor, most actions of AII, AIII are believed to be mediated by this receptor
-stimulates phospholipase C to increase Ca, causes constriction and increases MAPK (proliferative responses, like hypertrophy and tissue remodeling)
AT2 receptor
- does not activate phospholipase C or Ca signaling, but stimulates increases in NO and blocks MAPK activation.
- vasodilation and natriuresis
- opposes AT1 -medicated vasoconstriction and may be important in effects of AT1 receptor blockers. AT1 > AT2 in blood vessels.
Mas
mediates vasodilation, anti-inflammation, anti-cell proliferation opposes AT1 receptor mediated effects. increases Ca/NO
losartan
ARB (AT1 receptor blocker)
- primarily used for HTN, HF
- potent non-peptide competitive antagonist of AT1 receptors w high specificity
- lack some SE of ACE inhibitors, considered for patients that don’t tolerate ACE inhibitors
- higher affinity for AT1 than 2 or Mas
- don’t affect kininase II (enzyme that degrades bradykinin, identical to ACE)
- BP lowering may be medicated in part by residual AT2 receptor activation
valsartan
ARB (AT1 receptor blocker)
- primarily used for HTN, HF
- potent non-peptide competitive antagonist of AT1 receptors w high specificity
- lack some SE of ACE inhibitors, considered for patients that don’t tolerate ACE inhibitors
- higher affinity for AT1 than 2 or Mas
- don’t affect kininase II (enzyme that degrades bradykinin, identical to ACE)
- BP lowering may be medicated in part by residual AT2 receptor activation
candesartan
ARB (AT1 receptor blocker)
- primarily used for HTN, HF
- potent non-peptide competitive antagonist of AT1 receptors w high specificity
- lack some SE of ACE inhibitors, considered for patients that don’t tolerate ACE inhibitors
- higher affinity for AT1 than 2 or Mas
- don’t affect kininase II (enzyme that degrades bradykinin, identical to ACE)
- BP lowering may be medicated in part by residual AT2 receptor activation
irbesartan
ARB (AT1 receptor blocker)
- primarily used for HTN, HF
- potent non-peptide competitive antagonist of AT1 receptors w high specificity
- lack some SE of ACE inhibitors, considered for patients that don’t tolerate ACE inhibitors
- higher affinity for AT1 than 2 or Mas
- don’t affect kininase II (enzyme that degrades bradykinin, identical to ACE)
- BP lowering may be medicated in part by residual AT2 receptor activation
role of Ang-(1-7) in ARB use
-BP lowering effects of ARBs may be mediated in part via increased prod of Ang-(1-7)
SE of ARBs
-hypotension, hyperkalemia, ARF (esp in patients w renal insufficiency, AII/AIII maintain GFR). contraindicated in pregnant/nursing mothers
captopril
ACE inhibitors
uses: antihypertensive (esp essential HTN), LV systolic dysfuntion (reduces mortality), MI (reduces mort), HF (reduces mort)
enalapril
ACE inhibitors
uses: antihypertensive (esp essential HTN), LV systolic dysfuntion (reduces mortality), MI (reduces mort), HF (reduces mort)
lisinopril
ACE inhibitors
uses: antihypertensive (esp essential HTN), LV systolic dysfuntion (reduces mortality), MI (reduces mort), HF (reduces mort)
adverse effects of ACE inhibitors
captopril, enalapril, lisinopril
-same as ARBs: hypotension, hyperkalemia, ARF, plus dry cough and agioedema due to bradykinin
role of Ang-(1-7) in ACEI actions
-bp lowering effects of ACEIs may be mediated in part via increased production of Ang-(1-7), this is a result of loss of ACE mediated degredation of Ang-(1-7). Also loss of conversion of Ai to AII would 1. lead to more AI for synthesis of Ang-(1-7) and more release of renin which would generate more AI
aliskiren
non-peptide based renin inhibitor that is approved for rx of essential HTN
-same SE of ARBs and ACEI plus GI/allergic symptoms
effect of RAS blockade in normotensive pt
no effect, unless Na depleted
is the effect of RAS blockade dependent on high renin in HTN patients
no
-also works w renal disease/obstruction HTN
local RAS vascular smooth muscle
provides local intrinsic control
local RAS in brain
function as neurotransmitter, regulation of SNS, ADH release, regulation of arterial pressure and metabolism
plasma kallikrein vs tissue kallikrein
plasma kallikrein activates HMW, bloodstream kininogen to bradykinin; tissue kallikreins convert LMW kininogen to kallidin, which can convert to bradykinin
bradykinin
CV effects
t1/2 15 sec, acts where formed, autocoid causing vasodilation
- predominant kinin in blood
- potent vasodilator of arteriorles via NO and eicosanoids which lower BP
- increase capillary permeability
- directly stimulate sympathetic ganglia
- stimulate EPI release
what activates kallikreins
viruses, inflammation, cell death
in normotensive persons, role of bradykinin
-important in modulating Pa in hypertensive situations but it does not contribute to maintenance of basal Pa in normotensive agents
bradykinins on large arteries and veins
constriction
bradykinin other effects
- glandular secretion [salivary glands, pancreas functional vasodilation for secretion]
- inflammation (edema, increased BF, elevated kinin in various inflammatory situations)
- pain, stim sensory neurons, releases neuropeptides
kinin receptors
all G pro coupled receptors
b2 agonists (not beta)
bradykinin and kallidin are equally effective
-mediates majority of effects of BK
-activates PLC, which increases Ca and leads to pain, contraction, NO
-activates PLA2 leads to eicosanoids (prostaglandins)
vasodilation is mediated by NO and prostaglandin production
B2 antagonists
-are being developed for rx pain, asthma, chronic inflammatory diseases
(bradycor)
-others: peptide and nonpeptide
B1 receptor
- prefers a diff form of bradykinin (des-Arg bradykinin)
- mediates contraction of vascular smooth muscle
