Renin Angiotensin System where Angiotensin – II is an octapeptide generated in the plasma from a precursor plasma α2 – globulin called Angiotensinogen Angiotensin – II is involved in electrolyte balance, Blood volume balance, and pressure hemostasis. Angiotensin – II is responsible for Vasoconstriction, Na+ and water retention ( kidney ) and Aldosterone secretion ( adrenal cortex)

Circulating renin-angiotensin system

The amount of renin in plasma acts as the limiting factor for Angiotensin II generation. The plasma t½ of renin is 15 mins. It converts Angiotensinogen to Angiotensin I and The biological potency of Ang I is only 1/100  that of Ang II, but it is rapidly converted into Angiotensin  II by ACE which is a dipeptidyl carboxypeptidase. Circulating Ang II has a short t½ (1 min). The first degradation product from Angiotensin II is Angiotensin III and the second product produced is IV. Both this transformation is by Aminopeptidases. Angiotensinases converts Ang III and Ang IV to Inactive fragments

Tissue (local) renin-angiotensin systems :

Extrinsic local RAS: Blood vessels can also produce Angiotensin II apart from circulation

Intrinsic local RAS: Many tissues can also produce all components of the Renin-Angiotensin System, eg: Heart, Blood vessels, Brain, Kidneys, Adrenals. Here the system regulates cell growth, cell death, remodeling, fibrosis.

Renin & Prorenin activation
  • Circulating RAS synthesize – RENIN
  • Local RAS tissues synthesize  -PRORENIN

(concentration of prorenin and renin in circulation = 5 to 10 : 1 )  Prorenin is activated by Enzymatically and Non-enzymatically. 

Enzymatic activation – proteases like proconvertase-1 and Cathepsin B cut off the ‘propeptide’ to produce renin. This makes catalytic exposion of renin. This is a irreversible activation. 

Nonenzymatic activation – occurs by binding of prorenin to (PRR) (Pro) renin receptor.This binding brings about a conformational change, the ‘propeptide’ segment detached and the catalytic domain is exposed. This activation is reversible. While renin binds to PRR, augmentation of catalytic activity of renin into several folds happens. In local RAS Nonenzymatic activation of prorenin plays a major role, the effects of prorenin exerted through 2 pathways
Actions Of RAS
         1.CVS – Prominent action is Vasoconstriction ( both arterioles and venules )
                             This Vasoconstriction promotes the movement of fluid from vascular to the extravascular compartment
                            – Injected Ang II is much more potent than NA as a pressor agent
                            – Causes rise in BP by its renal effects promoting Na+ and water reabsorption
                            – Increases Myocardial Contraction by promoting Ca2+ influx
                            – Cardiac output is reduced and Cardiac work is increased as the peripheral resistance increases 
                            – Induces Hypertrophy, Remodeling of muscle mass, Fibrosis
          2. Adrenal cortex
                    – Enhance the synthesis and release of Aldosterone
                    – Aldosterone promotes Na+ reabsorption and K+/H+ excretion ( in distal tubule )
          3. Kidney
                         – Promotes Na+/ H+ Exchange –> Increased  Na+, Cl-, HCO3- reabsorption ( in proximal tubule )
                         – Reduces renal blood flow and GFR –> Na+ and Water retention
         4. CNS – Induce Drinking behaviour and ADH release.
Angiotensin Receptors:
Specific Ang II receptors are present on the surface of target cells. Two sub-types have been differentiated pharmacologically.
  • AT1 – Losartanis a selective Antagonist 
  • AT2 – PS123177 is a selective Antagonist
Pathophysiological Roles:
1. Mineralocorticoid secretion :
 Ang II and Ang III is the physiological stimulus for aldosterone secretion from the adrenal cortex.
 2. Blood volume, pressure and electrolyte hemostasis:
Changes that lower blood volume or blood pressure, or decrease Na+ content induce renin release by three mechanisms.
  •  Intrarenal baroreceptor pathway: These decrease afferent glomerular arterioles tension and it operates via increased production of prostaglandins (PGs) and stretches sensitive ion channels.
  • Macula densa pathway: Macula densa cells triggers this pathway. It has been found that COX-2 and neuronal nitric oxide synthase (nNOS) are induced in macula densa cells. These induce the release of PGE2 and PGI2. The locally released PGs act on juxtaglomerular cells to promote renin secretion.
  •  Beta adrenoceptor pathway: Baroreceptor and other reflexes that increase sympathetic impulses to JG cells activate Beta1 adrenoceptors expressed on their surface –> increased intra- cellular cAMP triggers renin release.
Continues release of Renin leads to an increase in Angiotensin II this inturn cause rise in BP by Vasoconstriction and also causes Na+ and water retention. Then renin release is decreased internally by
  1. Long loop negative feedback mechanism
  2. Short loop negative feedback mechanism
Renin release enhancers
        • ACE inhibitors, 
        • AT1 Antagonist, 
        • Vasodilators, 
        • Diuretics, 
        • Loop diuretics 
Renin release inhibitors
        • Central Sympatholytics
        • Beta blockers
        • NSAIDs
        • COX – 2
 Inhibition of renin – Angiotensin system
  1.  Sympathetic blockers – Beta-blockers, adrenergic neuron blockers, central Sympatholytics 
  2.  Direct renin inhibitors – e.g. aliskiren
  3.  Angiotensin converting enzyme inhibitors – e.g. captopril
  4.  Angiotensin receptor blockers – e.g. losartan
  5.  Aldosterone Antagonist – e.g. spironolactone

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