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 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

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