Lecture 13 Nitric Oxide & H2S Flashcards
How is Nitric Oxide Formed
From L-arginine and Oxygen
What else is Nitric Oxide known as
EDRF
Nitric Oxide Synthase (NOS)
What are the three different enzymes
Endothelial (eNOS)
Neuronal (nNOS)
Inducible (iNOS)
Endothelial (where)
Constitutive
Endothelial Cells
Leukocytes
Platelets
Mast Cell
Neuronal (where)
Constitutive
Neurons (CNS & PNS)
Mast Cells
Inducible (where)
Inducible (By inflammation stimulus)
Macrophages
Neutrophils
Which isoform of Nitric Oxide Synthase generates the most NO
Inducible
L-arginine-NO Pathway (Process that activates NOS)
Ach, bradykinin, substance P, etc activates receptor –> Releases more calcium –> Activates Calmodulin –> Activates an inactive NOS (Mechanical Shear Stress also contributes to activation) in Endothelial cells
L-arginine-NO Pathway (Process that activates GC)
Active NOS converts Arginine + O2 into Citrulline + NO –> NO activates Guanylyl Cyclase in smooth muscle cells
L-arginine-NO Pathway (Process that causes relaxation)
Active Guanylyl Cyclase converts GTP into cGMP –> cGMP causes relaxation
What kind of dimers are NOS isoforms
Homodimers
What cofactors are required for Constitutive Isoforms
NADPH
Flavin Adenine Dinucleotide
Flavin Mononucleotide
Heme
TH4
Ca2+/Calmodulin
What cofactors are required for Inducible Isoforms
NADPH
Flavin Adenine Dinucleotide
Flavin Mononucleotide
Heme
TH4
NADPH (NO Function)
Source of electrons
FAD/FMN
Takes electrons from NADPH and gives it to heme domain
Heme
Heme Domain takes electron from FAD/FMN
Also facilitates dimer formation
Ca2+/Calmodulin
Facilitates the transfer of electrons
Tetrahydrobiopterin (TH4)
Facilitates dimer formation
What does NO effect
Binds other enzymes that contain heme
S-Nitrosylation to thiol groups
Cysteine
Glutathione
Albumin
Deamination of DNA bases
Converts GTP into cGMP
What does cGMP do
Sends signals further downstream activating:
Ion Channels - Cyclic nucleotide gated
Protein Kinases - Phosphorylates other things
Phosphodiesterases - Increase/Decrease cAMP
How is cGMP signalling terminated
PDE5 converts cGMP into 5’GMP
How is NO inactivated
Binding Hemoglobin
Formation of nitrate and nitrile
Formation of peroxynitrite
Does NO have a long or short half life?
Short
What happens in binding of hemoglobin inactivation
Hb(Fe-O2) binds to NO
What happens in formation of nitrate and nitrite inactivation
NO reacts with Oxygen to form more stable compounds
What happens in formation of peroxynitrite inactivation
NO reacts with free radicals
Highly reactive can cause some damage
eNOS (effects)
Vascular
Decreases peripheral vascular resistance
Decreases blood pressure
Platelet Inhibition
eNOS (What activates it)
Ca2+ activated calmodulin, more Ca2+ means more activity
Fluid shear stress can act as stimuli to cause activation
Regulated by phosphorylation and are always active
nNOS (general effects)
Neuronal
nNOS (CNS effects)
Neurotransmitter
Learning and memory formation
nNOS (PNS effects)
Non-Adrenergic Non-Cholinergic (NANC) Neurotransmitter
Neurogenic Vasodilation
GI, Respiratory, Genital, Urinary Functions
Autonomic Innervation of Smooth muscle
nNOS (Neuroendocrine Effects)
Regulates/Influences:
Reproductive Behaviours
Aggression
Feeding
iNOS (effects)
Non-Specific Host Defence Mechanism
Expressed in response to bacterial endotoxins
Regulation of iNOS
Regulated at the transcription level
iNOS mechanisms of defence
Nitration of nucleic acids
Binding of Heme Enzymes
Binds mitochondrial enzymes that are needed for respiration
Where are iNOS constitutively expressed
Kidney, Liver, Lung
What inhibits iNOS expression
Glucocorticoids
Excess iNOS, how to treat?
Inflammatory Conditions (Meningitis, Rheumatoid Arthritis)
No clinical drugs
Glyceryl Trinitrate (Nitroglycerin)
NO Donor
Activates Smooth Muscles, Increase cGMP
Decrease Heart Rate
Nitroprusside
NO Donor
Decrease Heart Rate
Nebivolol
Selective beta 1 antagonist
Increases NO production
Decrease Heart Rate
Statins
Lowers Cholesterol
Increase NO production
Decrease Heart Rate
Sildenafil
PDE5 Inhibitors
Prevents termination of cGMP
This inhibition causes vasodilation –> Increases Blood Flow
Tadarafil
PDE5 Inhibitors
Prevents termination of cGMP
This inhibition causes vasodilation –> Increases Blood Flow
How do newborns handle pulmonary hypertension
Inhale NO to lower blood pressure
Carbon Monoxide
At low concentration has vasodilator effects
Role in CNS
Produced by heme oxygenase
Hydrogen Sulfide
At low concentrations has vasodilator and anti-inflammatory effects
Produced from cysteine
