NITRIC OXIDE & INHIBITORS
Prof. Dr. Zeliha Yazıcı
 NO is produced by many cells
 is found in almost all tissues
 Exogenous donors of NO: nitrates, nitrites, nitroprusside,
nitrosothiol, furoxans, sydnoimines
Synthesis
N
NO
O ddoonnoorrss
N
NO
OS
S
LL--aarrggiinniinnee
N
NO
O ++ LL--C
Ciittrruulllliinnee
N
NA
AD
DP
PH
H,, O
O22
G
Guuaannyyllyyll ccyyccllaassee
((FFee))
G
ccG
GTTP
P
GM
MP
P
NADPH: nicotinamide adenine dinucleotide phosphate
Isoform of Nitric oxide synthase (NOS)
nNOS (neuronal): neuronal, epithelial cells, Ca dependent
iNOS (inducible): macrophages, smooth muscle cells
eNOS (endothelial): endothelial cells, Ca dependent
Inhibitors
NOS inhibitiors: NG-monomethyl-L-arginine (L-NMMA), NGNitro-L-arginine methyl ester (L-NAME), 7-Nitroindazole,
S-Methylthiocitrulline
Nitric oxide scavenger: Heme
Inactivation
 NO is inactivated by heme and superoxide
 interaction of NO with superoxide → peroxynitrite (ONOO-)→
tissue damage, inactivation of sulfhydryl-bearing enzymes
regulated by glutathione
 interaction of NO with glutathione → S-nitrosoglutathione
(long-lived carrier of NO)
 Glutathione is decreased in diabetes mellitus and
atherosclerosis (increased cardiovascular complications)
 Reperfusion → ↑production of free radicals →↓NO formation
→ ischemia
Cardiovascular system
 Ach & other endothelium dependent vasodilators release NO
 A vasodilator
 A potent inhibitor of neutrophil adhesion
 NO donors protects against ischemia & reperfusion mediated
endothelial dysfunction
Pulmonary System
 NO inhalation decreases pulmonary arterial pressure and
improves blood oxygenation
 NO may have a role in relaxing airway smooth muscle acting
as a bronchodilator
 NO improves cardiopulmonary function in pulmonary
hypertension and acute respiratory distress syndrome (INO
max, 100, 800 ppm gas)
The Central Nervous System
 NO may have a role as a neurotransmitter and/or as a
modulator of ligand–gated receptors
 May be useful in neuronal degeneration
 Postsynaptic release of NO following NMDA receptor
activation may initiate presynaptic transmitter release of
glutamate, resulting in opening of the Ca++ channels and
activation of NOS
 NO may have a role in sort- and long term potentiating
effects on excitatory amino acids in brain development and
learning
 Neuronal NOS-1 inhibitors have significant antinociceptive
effects in human and animals, reduce cerebral blood flow
and the size of cerebral infarcts
 NOS-2 has been implicated in degenerative neurologic
condition (eg, Alzheimer’s disease, MS, Huntington’s
disease)
 High level of NO can cause destruction of photoreceptor cells
in the retina (cGMP ↑)
 NO and cGMP have a role in epileptic seizures
The Peripheral Nervous System
 NANC neurons release NO which leads to relaxation of the
cavernosal smooth muscle. Smooth muscle tone is the prime
determinant of the degree of erection
Inflammation
 NOS-3 inhibitors have a dose-dependent protective effect in
inflammation suggesting that NO promote edema and
vascular permeability (activating COX-2)
 NOS-2 inhibitors have protective effect in arthritis
 NO and NOS-2 increase in psoriasis lesions, asthmatic
airway epithelium and inflammatory bowel lesions
 NO stimulates immune cell function
Platelets
 NO has beneficial effect on blood coagulation
 NO inhibits platelet adhesion and aggregation
 NO enhances fibrinolysis via an effect on plasminogen
Organ transplantation
 NO is a cytoprotective agent by reducing free radical toxicity
and inhibiting platelet adhesion and aggregation to the
vascular wall
 High level NO may be harmful during acute organ rejection
(Inhibition of NO synthesis prolongs graft survival)
Septic shock
 The oxidative product of NO (nitrate) increases in gramnegative bacterial infection
 Lipopolysaccharide component from bacterial wall activate
NOS-2 resulting in exaggerated hypotension, shock, and
possible death
Atherosclerosis
 Vascular plaque formation leads to reduced NO formation
and endothelium-dependent vasodilator responses.
 NO carrier and donors and cGMP analogs inhibit smooth
muscle cell proliferation
 NO may act as an antioxidant, blocking the oxidation of LDL
and thus preventing the formation of foam cells in the
vascular wall