VASCULAR SYSTEM 2 - VASODILATION
NITRIC OXIDE
• widely produced in the body - released by endothelial layer - specific to vasculature
• transmitter in the central and peripheral nervous system
• short half life - 10-60s
• imbalance of NO production is implicated in many clinical conditions
◦ hypertension/atherogenesis
• actions of NO
◦ Immune function
▪ Inhibit platelet adhesion and aggregation
▪ Inhibit monocyte adhesion and migration
▪ Inhibit smc and fibroblast proliferation
▪ (Host defence: Contributes to cytotoxic killing mechanisms of immune
cells)
◦ vascular function
▪ induces SMC relaxation via activation of cGMP dependent protein kinases in
smc
• synthesis and breakdown of NO
◦ Synthesised by the oxidation of L-Arginine
◦ oxidised to L-citruline + NO
◦ Cofactors: NADPH, BH4, oxygen, Calmodulin
• NO is short acting
◦ oxidised to nitrate/nitrite
▪ Oxygenated haemoglobin
▪ Molecular Oxygen
▪ Superoxide anions
◦ Forms nitrosothiols – release NO over a longer time period
• Synthesis and breakdown of NO:
• Nitric oxide synthases: 3 isoforms
◦ eNOS - endothelial
◦ nNOS - neuronal
◦ iNOS - inducible NOS - in disease states
• Basal production of NO - low levels needed to relax the vessels slightly to
prevent hypertension
• Caveolae - cholestorol rich regions in bilayer
◦ eNOS localised in Caveolae (Cholesterol rich)
◦ Associates with Caveolin-1 protein
▪ (reversible interaction)
, ▪ (inhibitory)
• Action on smc:
◦ NO binds to soluble guanylate cyclase in smc leading to activation of cGMP
◦ cGMP activates cGMP-dependent protein kinases
◦ Ca sequestration and reduced intracellular Ca
◦ Smc relaxation
• Action inhibited by substrate analogues
◦ Eg. L-NMMA (N-monomethyl Larginine
◦ Eg. L-NAME (N-nitro L-arginine methyl ester)
NITRIC OXIDE
• widely produced in the body - released by endothelial layer - specific to vasculature
• transmitter in the central and peripheral nervous system
• short half life - 10-60s
• imbalance of NO production is implicated in many clinical conditions
◦ hypertension/atherogenesis
• actions of NO
◦ Immune function
▪ Inhibit platelet adhesion and aggregation
▪ Inhibit monocyte adhesion and migration
▪ Inhibit smc and fibroblast proliferation
▪ (Host defence: Contributes to cytotoxic killing mechanisms of immune
cells)
◦ vascular function
▪ induces SMC relaxation via activation of cGMP dependent protein kinases in
smc
• synthesis and breakdown of NO
◦ Synthesised by the oxidation of L-Arginine
◦ oxidised to L-citruline + NO
◦ Cofactors: NADPH, BH4, oxygen, Calmodulin
• NO is short acting
◦ oxidised to nitrate/nitrite
▪ Oxygenated haemoglobin
▪ Molecular Oxygen
▪ Superoxide anions
◦ Forms nitrosothiols – release NO over a longer time period
• Synthesis and breakdown of NO:
• Nitric oxide synthases: 3 isoforms
◦ eNOS - endothelial
◦ nNOS - neuronal
◦ iNOS - inducible NOS - in disease states
• Basal production of NO - low levels needed to relax the vessels slightly to
prevent hypertension
• Caveolae - cholestorol rich regions in bilayer
◦ eNOS localised in Caveolae (Cholesterol rich)
◦ Associates with Caveolin-1 protein
▪ (reversible interaction)
, ▪ (inhibitory)
• Action on smc:
◦ NO binds to soluble guanylate cyclase in smc leading to activation of cGMP
◦ cGMP activates cGMP-dependent protein kinases
◦ Ca sequestration and reduced intracellular Ca
◦ Smc relaxation
• Action inhibited by substrate analogues
◦ Eg. L-NMMA (N-monomethyl Larginine
◦ Eg. L-NAME (N-nitro L-arginine methyl ester)
