1. By the end of this lecture you will be able to: Recognize the role of NO in cellular communication. Classify the different NOS available Expand on its formation, actions termination and pharmacological modulation. Identify role of angiotensin in body homeostasis and local regulation. Explain its formation, target receptors, feedback regulatory actions, breakdown, intersection with the kinin system and pharmacological modulation. Part I

3. Is a highly diffusible stable gas Synthesis L-arginine + O 2 NO + Citrulline + H 2 O Nitric oxide synthase (NOS) NADPH, FAD, CaCAM Type I [n-NOS] Neuronal NOS Type III [E-NOS] Endothelial NOS Type II [I-NOS] Inducible NOS Cytosol of Neuronal cells Bound to membrane of endothelial cell [EC], platelets …etc. Cytosol of macrophage, neutrophil, kupffer cells … etc Constitutive Inducible Neuronal messenger Cytoprotective Relaxation of VSMC Cytoprotective Immunocytotoxicity NOS Isoforms Shear Stress or Agonists as; Ach, histamine, bradykinin, …..when bind to receptors  intracellular Ca activate eNOS NO formation EC= Endothelial Cells / VSMC= Vascular Smooth Muscle Cell

4. Action Activate PKG &  Ca Inactivate MLCK Prevent actin myosin cross link No contraction RELAXATION Endothelial Cell [EC] 1.Vasodilatation Diffuse to VSMC Binds soluble GC Change GTP to cGMP Site of formation Vascular Smooth Muscle [ VSMC] MLCK - Diffusion 2. Cytoprotection  platelet aggregation  inflammatory cell recruitment  Cholesterol deposition…etc. MLCK= Myosin Light Chain Kinase

5. Termination of action By formation of 1. Stable analogues with proteins containing SH …. 2. Free radical Peroxynitrite in oxidative stress By break down of its downstream signal cGMP by PDE to form GMP BV

6. Drugs modulating 1. Express eNOS: Statins, Estrogen CVS Cytoprotection 2. Act as NO donners: a. Nitrates >Venulodilators in angina b. Na Nitroprusside Arteriolar dilator in hypertension 3. Inhibit PDE = (Prevent breakdown of cGMP): Selective PDE 5 Inhibitors ; Sildenafil Erectile dysfunction

8. Other Proteolytic Enzymes Chymase Endoperoxidase A vasoconstrictor peptide Synthesis Precursor is Angiotensinogen ; a plasma  -globulin synthesized in the liver. Secreted by renal juxtaglomerular apparatus. HOW ? AT 1 AT 2 When Blood Pressure  or Blood flow  Renin is released The active form Vasoconstriction Lungs Endothelium & Brain Angiotensinogen (Ag)

9.  Inotropy  Chronotropy Action  Na retention  Hypertrophy  Fibrosis  Thirst  SNS activation Vasoconstriction  Remodeling =Hypertrophy  Fibrosis  H 2 O retention

10. AgII acted upon by peptidases aminopeptidases (angiotensinase) to Ag III [a less active] & then to fragmentation products Termination of action AT 1 VasoconstrictionVasodilatation AT 2 GP- Coupled Receptors Mechanism of action

11.  BF [  2 ] Drugs modulating INHIBITION OF RAAS SYSTEM is beneficial in treatment of: Hypertension (  hypertrophy) Heart Failure (  hypertrophy & fibrosis) Diabetics (Protect the kidney) Inactive metabolites

13. Bradykinin is a vasodilator peptide It is formed from by the action of Synthesis Action Vasodilatation Inflammation & Exudation Pain (sensory nerves) Exocrine gland secretion Termination of action Tissue Kallikrin Inactive metabolites Kininogen ACE & Neutral Endopeptidase (NEP) Plasma Kallikrin Bradykinin

14. Drugs modulating. NO L-arginine + O 2 NO + Citrulline + H 2 O (eNOS) Bradykinin Vasodilatation Inactive metabolites  

15. Inhibit activation of AgI to AGII + decrease degradation of bradykinin Difference between ACE Is & ARBs action Block action of AgII on AT1 in VSMCs that is causing vasoconstriction The AgII act on non-blocked AT2 on endothelial cells causing vasodilatation

16. Quiz? NO is an example of mediator that is: a.Stored in preformed granules b.Synthesized de novo c.Only inducible d. Vasoconstrictor

17. Quiz? Renin is: a.Secreted by the liver b.Changes angiotensin I to II c.Inhibited by alsikiren d. Activated by elevated blood pressure

18. Quiz? Bradykinin is responsible for: a.Vasoconstriction b.Pain sensation c.Endocrine gland secretion d.Skeletal muscle contraction

19. Quiz? ACE is: a.Responsible for activation of kininogen to bradykinin b.Responsible for activation of angiotensinogen to angiotensin I. c.Mostly concentrated in the kidney d.Inactivated by vasopetidase inhibitors.