Lecture 13 Nitric Oxide & H2S

Question 1

How is Nitric Oxide Formed

Answer 1

From L-arginine and Oxygen

Question 2

What else is Nitric Oxide known as

Answer 2

EDRF

Question 3

Nitric Oxide Synthase (NOS)

Question 4

What are the three different enzymes

Answer 4

Endothelial (eNOS)
Neuronal (nNOS)
Inducible (iNOS)

Question 5

Endothelial (where)

Answer 5

Constitutive
Endothelial Cells
Leukocytes
Platelets
Mast Cell

Question 6

Neuronal (where)

Answer 6

Constitutive
Neurons (CNS & PNS)
Mast Cells

Question 7

Inducible (where)

Answer 7

Inducible (By inflammation stimulus)

Macrophages
Neutrophils

Question 8

Which isoform of Nitric Oxide Synthase generates the most NO

Answer 8

Inducible

Question 9

L-arginine-NO Pathway (Process that activates NOS)

Answer 9

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

Question 10

L-arginine-NO Pathway (Process that activates GC)

Answer 10

Active NOS converts Arginine + O2 into Citrulline + NO –> NO activates Guanylyl Cyclase in smooth muscle cells

Question 11

L-arginine-NO Pathway (Process that causes relaxation)

Answer 11

Active Guanylyl Cyclase converts GTP into cGMP –> cGMP causes relaxation

Question 12

What kind of dimers are NOS isoforms

Answer 12

Homodimers

Question 13

What cofactors are required for Constitutive Isoforms

Answer 13

NADPH
Flavin Adenine Dinucleotide
Flavin Mononucleotide
Heme
TH4
Ca2+/Calmodulin

Question 14

What cofactors are required for Inducible Isoforms

Answer 14

NADPH
Flavin Adenine Dinucleotide
Flavin Mononucleotide
Heme
TH4

Question 15

NADPH (NO Function)

Answer 15

Source of electrons

Question 16

FAD/FMN

Answer 16

Takes electrons from NADPH and gives it to heme domain

Question 17

Heme

Answer 17

Heme Domain takes electron from FAD/FMN

Also facilitates dimer formation

Question 18

Ca2+/Calmodulin

Answer 18

Facilitates the transfer of electrons

Question 19

Tetrahydrobiopterin (TH4)

Answer 19

Facilitates dimer formation

Question 20

What does NO effect

Answer 20

Binds other enzymes that contain heme
S-Nitrosylation to thiol groups
Cysteine
Glutathione
Albumin
Deamination of DNA bases

Converts GTP into cGMP

Question 21

What does cGMP do

Answer 21

Sends signals further downstream activating:
Ion Channels - Cyclic nucleotide gated
Protein Kinases - Phosphorylates other things
Phosphodiesterases - Increase/Decrease cAMP

Question 22

How is cGMP signalling terminated

Answer 22

PDE5 converts cGMP into 5’GMP

Question 23

How is NO inactivated

Answer 23

Binding Hemoglobin

Formation of nitrate and nitrile

Formation of peroxynitrite

Question 24

Does NO have a long or short half life?

Answer 24

Short

Question 25

What happens in binding of hemoglobin inactivation

Answer 25

Hb(Fe-O2) binds to NO

Question 26

What happens in formation of nitrate and nitrite inactivation

Answer 26

NO reacts with Oxygen to form more stable compounds

Question 27

What happens in formation of peroxynitrite inactivation

Answer 27

NO reacts with free radicals Highly reactive can cause some damage

Question 28

eNOS (effects)

Answer 28

Vascular Decreases peripheral vascular resistance Decreases blood pressure Platelet Inhibition

Question 29

eNOS (What activates it)

Answer 29

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

Question 30

nNOS (general effects)

Answer 30

Neuronal

Question 31

nNOS (CNS effects)

Answer 31

Neurotransmitter Learning and memory formation

Question 32

nNOS (PNS effects)

Answer 32

Non-Adrenergic Non-Cholinergic (NANC) Neurotransmitter Neurogenic Vasodilation GI, Respiratory, Genital, Urinary Functions Autonomic Innervation of Smooth muscle

Question 33

nNOS (Neuroendocrine Effects)

Answer 33

Regulates/Influences: Reproductive Behaviours Aggression Feeding

Question 34

iNOS (effects)

Answer 34

Non-Specific Host Defence Mechanism Expressed in response to bacterial endotoxins

Question 35

Regulation of iNOS

Answer 35

Regulated at the transcription level

Question 36

iNOS mechanisms of defence

Answer 36

Nitration of nucleic acids Binding of Heme Enzymes Binds mitochondrial enzymes that are needed for respiration

Question 37

Where are iNOS constitutively expressed

Answer 37

Kidney, Liver, Lung

Question 38

What inhibits iNOS expression

Answer 38

Glucocorticoids

Question 39

Excess iNOS, how to treat?

Answer 39

Inflammatory Conditions (Meningitis, Rheumatoid Arthritis) No clinical drugs

Question 40

Glyceryl Trinitrate (Nitroglycerin)

Answer 40

NO Donor Activates Smooth Muscles, Increase cGMP Decrease Heart Rate

Question 41

Nitroprusside

Answer 41

NO Donor Decrease Heart Rate

Question 42

Nebivolol

Answer 42

Selective beta 1 antagonist Increases NO production Decrease Heart Rate

Question 43

Statins

Answer 43

Lowers Cholesterol Increase NO production Decrease Heart Rate

Question 44

Sildenafil

Answer 44

PDE5 Inhibitors Prevents termination of cGMP This inhibition causes vasodilation --> Increases Blood Flow

Question 45

Tadarafil

Answer 45

PDE5 Inhibitors Prevents termination of cGMP This inhibition causes vasodilation --> Increases Blood Flow

Question 46

How do newborns handle pulmonary hypertension

Answer 46

Inhale NO to lower blood pressure

Question 47

Carbon Monoxide

Answer 47

At low concentration has vasodilator effects Role in CNS Produced by heme oxygenase

Question 48

Hydrogen Sulfide

Answer 48

At low concentrations has vasodilator and anti-inflammatory effects Produced from cysteine