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- AT 1 and AT 2 Most effects of AngII are mediated by AT 1 receptors Role of AT2 2 receptors not well defined May counterbalance many effects of AT 1 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. Peripheral Vasoconstriction Enhancement of NE transmission  of NE reuptake  of NE response Ganglionic stimulation AT 1   SymPathetic Outflow  Baroreflex mediated  in sympathetic outflow CNS Rapid Pressor Response Blood Vessel

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 Ca 2+ channels  contractility  Central sympathetic tone  Release of CA from adrenals Facilitation of adrenergic transmission Baroreflex mediated  of sympathetic tone Net Effect Uncertain  HEART (+) (-)

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 AT 1 receptors Binding and blockade are often insurmountable- slow dissociation from AT 1 receptors ARBs induced receptor internalization Increase renin release and AngII levels like ACE inhibitors Candesartan IrbesartanEprosartan LosartanOlmesartanTelmisartan 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