by the end of this lecture you will be able to: recognize the role of no in cellular communication....
TRANSCRIPT
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.