Local (Tissue) Renin-Angiotensin System

1

• 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

2

• 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 receptorstwo 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

3

• 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

4
Rapid Pressor Response
AT1
CNS
Blood Vessel
Peripheral Vasoconstriction

• ? SymPathetic Outflow
• ? Baroreflex mediated ? in sympathetic outflow

?

• Enhancement of NE transmission
• ? of NE reuptake
• ? of NE response
• Ganglionic stimulation

5

• 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

6

• 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

7

• 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

8

• 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

9

• 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

10
Opening of voltage gated Ca2 channels??
contractility
(-)
? Central sympathetic tone
()
HEART
Baroreflex mediated ? of sympathetic tone
? Release of CA from adrenals
?
Facilitation of adrenergic transmission
Net Effect Uncertain
11

• Inhibitors of RAS
• ACE inhibitors (ACEIs)
• Angiotensin receptor blockers (ARBs)
• Direct renin inhibitors (DRIs)

12

• 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

13

• 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

14

• 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

15

• 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
  hypotension- ACE inhibitors to be stopped during
  pregnancy

16

• 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

17

• 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

18

• Uses of ARBs
• Essential hypertension
• Irbesartan losartan- diabetic nephropathy
• Losartan- stroke prophylaxis
• Valsartan- heart failure

19

• 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