By the end of this lecture you will be able to:Recognize the role of NO in cellular communication.Classify the different NOS availableExpand 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

Is a highly diffusible stable gas

Synthesis

  L-arginine + O2        NO + Citrulline + H2O

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 ofNeuronal cells

Bound to membrane of endothelial cell [EC], platelets …etc.

Cytosol of macrophage, neutrophil, kupffer cells … etc

Constitutive

Constitutive Inducible

Neuronal messengerCytoprotective

Relaxation of VSMCCytoprotective

Immunocytotoxicity

NOS Isoforms

Shear Stress or Agonists as; Ach, histamine, bradykinin, …..when bind to receptors intracellular Ca activate eNOS NO formation

Role of NO in blood vessels Relaxation of VSMCs (Vasodilatation) + Cytoprotection

Action

Activate PKG &Ca Inactivate MLCKPrevent actin myosin bindingNo contractionRELAXATION

Endothelial Cell [EC]

1. VasodilatationDiffuse to VSMCBinds soluble GCChange GTP to cGMP

Site of formation

Vascular Smooth Muscle [ VSMC]

MLCK-

2. Cytoprotection on ECsplatelet aggregation, inflammatory cell recruitment Cholesterol deposition…etc.

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

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. Prevent breakdown of PDE: Selective PDE5 Inhibitors; Sildenafil Erectile dysfunction

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 ?

AT1 AT2

When Blood Pressure Renal SN & Blood flow Renin is released

The active form

Vasoconstriction

Lungs Endothelium & Brain

Angiotensinogen (Ag)

InotropyChronotropy

Action

ALDOSTERONEALDOSTERONE

Ag IIAg II

Na retention

HypertrophyFibrosis

ADHADH

Thirst

SNS activation

Vasoconstriction

Remodeling =HypertrophyFibrosis

Ag IIAg IIAg IIAg II

Ag IIAg II

Ag IIAg II

Ag IIAg II

AgII acted upon by peptidases

aminopeptidases (angiotensinase)

to Ag III [a less active] & then to fragmentation products

Termination of action

Ag IIAg II

AT1 R; GP receptor coupled to q PKC + Ca CAMK

AT1

SNSN BF [2 ] BF [2 ]

PropranolPropranololol

ClonidiClonidinene

Drugs modulating

RENIN InhibitorsRENIN InhibitorsAliskirenAliskiren

ACE InhibitorsACE InhibitorsRamiprilRamipril

ARBsARBsCandisartianCandisartian

ADOSTERONE RAsADOSTERONE RAsSpirinolactoneSpirinolactoneEplerenoneEplerenone

VASOPEPTIDASE IsVASOPEPTIDASE IsOmapatrilatOmapatrilat

INHIBITION OF RAAS SYSTEM is beneficial in treatment of:

Hypertension (hypertrophy)Heart Failure (hypertrophy & fibrosis) Diabetics (Protect the kidney)

Bradykinin is a vasodilator peptides 

Synthesis

Action Vasodilatation Inflammation & Exudation Pain (sensory nerves) Exocrine gland secretion

Termination of action

KallidinBradykinin

Plasma Kallikrin

TissueKallikrin

Aminopeptidase

Inactive metabolites

KininogenFrom liver

ACE & Neutral Endopeptidase

(NEP)

Drugs modulating . Action bradykinin mediated pain NSAIDs NSAIDs

Breakdowntheir concentration ACE InhibitorsACE Inhibitors VASOPEPTIDASE IsVASOPEPTIDASE Is

Antihypertensive drugs

AT1

AT2

ACE InhibitorsACE InhibitorsRamiprilRamipril

ARBsARBsCandisartanCandisartan

Inhibit activation of AgI to AGII + decrease degradation of bradykinin

Block action of AgII on AT1 in VSMCs that is causing vasoconstrictionThe AgII act on non-blocked AT2 on endothelial cells causing vasodilatation

Difference between ACE Is & ARBs action

Quiz?

NO is an example of mediator that is:

a.Stored in preformed granulesb.Synthesized de novoc.Only inducibled. Vasoconstrictor

Quiz?

Renin is:

a.Secreted by the liverb.Changes angiotensin I to IIc.Inhibited by alsikirend. Activated by elevated blood pressure

Quiz?

Bradykinin is responsible for:

a.Vasoconstrictionb.Pain sensationc.Endocrine gland secretiond.Skeletal muscle contraction

Quiz?

ACE is:

a.Responsible for activation of kininogen to bradykininb.Responsible for activation of angiotensinogen to angiotensin I.c.Mostly concentrated in the kidneyd.Inactivated by vasopetidase inhibitors.