Transcript Renin-Angio Sys

Local (Tissue) Renin-Angiotensin System
•Important for its role in hypertrophy, inflammation,
remodelling and apoptosis
•Binding of renin or pro-renin to pro-renin receptors
located on cell surface
•Present in many tissues like brain, pituitary blood
vessels, heart, kidney, adrenal glands
•Extrinsic local RAS: in vascular endothelium of these
tissues
•Intrinsic local RAS: tissues having mRNA expression
•Number of enzymes that act as alternative pathway for
conversion of angiotensinogen to AngI or directly to
AngII
•Enzymes are: cathepsin, tonin, cathepsin G,
chymostatin sensitiveAngII generating enzyme and
heart chymase
•Angiotensin receptors:two typesAT1 and AT2
Most effects of AngII are mediated by AT1 receptors
Role of AT22 receptors not well defined
May counterbalance many effects of AT1 activation
Functions of RAS
•Effects of AngII on CVS include:
Rapid pressor respone-  peripheral resistance
Slow pressor response- via decrease in renal excretion
and production of endothelin-1
Vascular and cardiac hypertrophy and remodeling
Rapid Pressor Response
AT1
Blood
Vessel
Peripheral
Vasoconstriction

Enhancement of NE
transmission
• of NE reuptake
• of NE response
•Ganglionic stimulation
CNS
• SymPathetic
Outflow
• Baroreflex
mediated  in
sympathetic
outflow
•Brain contains all components of RAS
•Brain is affected by both circulating AngII and AngII
formed within the brain
•Action of AngII on brain causes:
Increased central sympathetic tone
Dipsogenic effect (thirst)
•Release of catecholamines from adrenal medulla: AngII
depolarises the chromaffin cells of adrenal medulla and
causes release of adrenaline
Slow Pressor Response:
•Produced by effect on the kidneys
•AngII:
Reduces urinary excretion of Na+ and water
Increases excretion of K+
Stimulates Na+/H+ exchange in proximal tubule due to
which Na+, Cl- and bicarbonate reabsorption increases
Increases expression of Na+-glucose symporter in
proximal tubule
Directly stimulates Na+-K+-2Cl- symporter in thick
ascending limb
•Proximal tubule secretes angiotensinogen and the
connecting tubule secretes renin
•Paracrine tubular RAS? Functions?
•AngII stimulates zona glomerulosa of adrenal cortex to
increase the synthesis and secretion of aldosterone
•Also auguments its response to other stimuli like
ACTH, K+
•Aldosterone acts on distal and collecting tubules to
cause retention of Na+ and excretion of K+ and H+
•Stimulatory effect of AngII on aldosterone secretion
depends on plasma concentrations of Na+ and K+
•Release of aldosterone is enhanced in cases of
hyponatremia or hyperkalemia and vice versa
•Effect on glomerular filtrate:
Constriction of afferent arterioles reduces
intraglomerular pressor and tends to reduce GFR
Contraction of mesangial cells decreases the capillary
surface area within the glomerulous and tends to
decrease GFR
Constriction of efferent arterioles increases the
intraglomerular pressor and tends to increase GFR
Normally, GFR is slightly reduced by AngII
•Vascular and cardiac hypertrophy and remodeling:
Cells involved- vascular smooth muscle cells, cardiac
myocytes and fibroblasts
Stimulates migration, proliferation and hypertrophy of
vascular smooth muscle cells
Increases extracellular matrix production by vascular
smooth muscle cells
Causes hypertrophy of cardiac myocytes
Increases extracellular matrix production by cardiac
fibroblasts
Opening of voltage gated Ca2+
channels contractility
 Central sympathetic tone
(+)
(-)
HEART
 Release of CA from adrenals
transmission

Facilitation of adrenergic
Baroreflex mediated  of
sympathetic tone
Net Effect Uncertain
Inhibitors of RAS
•ACE inhibitors (ACEIs)
•Angiotensin receptor blockers (ARBs)
•Direct renin inhibitors (DRIs)
ACE Inhibitors:
•Inhibit conversion of AngI to AngII
•Decrease BP, Increase Na+ excretion from kidney
•Increase levels of bradykinin which stimulates
formation of PGs- lower BP
•Increase circulating levels of natural stem cell
regulator- cardioprotective effect ?
•Increase renin release and formation of AngI due to
inhibition of short loop negative feed back (AngII)
•AngI accumulates & metabolized to vasodialtor
peptides
•Healthy persons with normal sodium: ACE inhibitors
have minor effects on BP
•Salt depleted person: substantial lowering of BP
•Mainly eliminated by kidney so dosage should be
adjusted in compromised renal functions
•Marked lowering of BP in patients with increased
renin activity, adjust dose
•All ACE inhibitors are prodrugs
Uses of ACE Inhibitors:
•Essential hypertension
•Left ventricular systolic dysfunction: prevents or delays
progression of heart failure
•Acute MI
•High risk patients of cardiovascular disorders
•Diabetes mellitus with renal failure- has renoprotective
effects in type I D. mellitus
•Scleroderma renal crisis
ADRs:
•Hypotension- first dose in high renein patients
•Cough- due to accumulation of bradykinin, substance
P and/or PGs in lungs. Thromboxane, aspirin and iron
helpful
•Hyperkalemia in patients of renal failure/D.mellitus
•Acute renal failure- in patients of renal artery stenosis,
single renal artery or heart failure - due to dilatation of
efferent arteriole
•Fetopathic effect: may be due to fetal hypotensionACE inhibitors to be stopped during pregnancy
•Skin rash
•Angioedema: in some patients, disappears after
stopping ACE inhibitors
Interactions:
•NSAIDs may reduce antihypertensive effect
•K+ sparing diuretics and K+ supplements may
precipitate hyperkalemia
ARBs:
•Competitively Bind to AT1 receptors
•Binding and blockade are often insurmountableslow dissociation from AT1 receptors
ARBs induced receptor internalization
•Increase renin release and AngII levels like ACE
inhibitors
Candesartan
Irbesartan
Eprosartan
Losartan
Olmesartan
Telmisartan
Vasartan
Uses of ARBs:
•Essential hypertension
•Irbesartan & losartan- diabetic nephropathy
•Losartan- stroke prophylaxis
•Valsartan- heart failure
Direct Renin Inhibitors:
•Aliskiren- approved drug
•Competitive inhibitor of renin
•Reduces formation of AngII but increases plasma renin
conc. due to loss of short loop negative feed back
•Dose-dependant decrease in BP
•Decreases plasma aldosterone levels and enhances
natriuresis
•Single oral dose 150-300 mg/day
•Used for treatment of hypertension