Lecture 14 Flashcards
What happens when the endothelium is removed?
Acetylcholine results in contraction
What happens when endothelium is present?
Acetylcholine results in relaxation
What was discovered when the epithelium was present?
EDRF - endothelium derived relaxing factor
What was the EDRF identified as?
The gas nitric oxide
Why did Robert Furchgott, Louis Ignarro and Ferid Murad win the normal prize in 1998?
For their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system
What does NO generate?
Smooth muscle relaxation via stimulation of cGMP production
How is NO broken down?
It is rapidly broken down by free radicals (O2-) and by haemoglobin
What is the NO signalling pathway synthesised from?
L-arginine by eNOS (endothelial nitric oxide synthase)
What does NO toncially control?
Vascular resistance
How can you inhibit eNOS?
With L-NMMA which Inhibits blood flow by 50%
What is the inhibition of eNOS reversed by?
L-arginine
How often is NO released?
It is released continuously to control blood flow
What is the most important control of NO release?
SHEAR STRESS is the signal, not flow
What does an increase in NO synthesis increase?
It is increases with blood viscosity at a constant flow rate
What does the degradation of glycocalyx =
Reduction in flow-induced NO production
What is the stress signal transduced by?
Endothelial glycocalyx (integrins)
What do integrins activate?
Phosphatidyl inositol 3 kinase
What is the mechanisms for shear stress-induced NO production?
Stress signal is induced by endothelial glycocalyx,
Which actuates phosphatidyl inositol 3 kinase
Which phosphorylates protein kinase B
Which phosphorylates eNOS
And increase eNOS activity
What does NO couples flow in?
Arterioles and conduit arteries
What is metabolic hyperaemia?
Local control of blood flow
What is the pathway for NO flow in arterioles and conduit arteries?
Vasodilation of arterioles,
Increase flow rate in upstream conduit artery,
Increase shear stress
Increase NO release
What is another mechanism of endothelium-dependent relaxation?
Acetylcholine causes arterial relaxation and hyperpolarisation of smooth muscle cells
What is another way for endothelium-dependent relaxation?
Inhibition of eNOS and PGI2 production which blocks later relaxation phase
What is the early phase of hyperpolarisation and relaxation mediated by?
Endothelium dependent hyperpolarising factor (EDHF)
What causes hyperpolarisation of the endothelial cell?
An agonist
How can hyperpolarisation spread through the cell?
Via gap junctions
What are candidate EDHFs?
K+, EET, hydrogen peroxide, c-natriuretic peptide
What are the agonists that cause hyperpolarisation through the cell?
Thrombin, bradykinin, acetylcholine
What are some examples of endothelium derived vasoactive substances?
Nitric oxide, EDHF, prostacyclin (PGI2), endothelin
What does the EDHF factor do?
Causes vasodilation in small vessels, especially arterioles
What is prostacyclin derived from?
Arachidonic acid
What does prostacyclin do?
Vasodilation and prevents platelet adhesion to endothelial cells
Describe endothelin?
It’s a peptide, contributes to vasoconstriction and has a small contribution to basal vascular tone
Do NO, EDHF and PGI2 vary?
They vary between arterioles of different diameters and from different vascular beds
Where is NO found in disease?
In essential hypertension, secondary hypertension, diabetes 1,2 and atheroma and dyslipidemia
What is the role of NO in essential hypertension?
Abnormal production of NO implicated
What is secondary hypertension?
Increased release of asymmetric dimethylarginine from damaged kidney
What is the role of NO in diabetes 1 and 2?
Associated with a decreased NO production and decreased NO induced relaxation. Evidence of decreases insulin-mediated NO production
What is the role of NO in septic shock?
Increase stimulation of iNOS production in macrophages and endothelial cells = massive vasodilation and increase in capillary permeability
What does iNSO mean?
Inducible NOS
What does septic shock result in?
Fall in blood pressure often fatal
What could reverse hypotension?
L-NMMA treatment
Describe the mechanism involved in NO formation and vasodilation?
Increases in ca2+ in endothelial cells induced by stimuli such as shear stress, blood flow and binding of agonists leads to formation of a ca2+ calmodulin complex which activates NO
What is eNOS response for?
Most of the vascular NO production
What happens to eNOS in a pathological state?
Becomes a potential ROS (reactive oxygen species) generator due to various oxidative stress
What are the 3 different signalling pathways that regulate vascular tone?
Ca2+ signalling pathway, NO-cGMP, vascular signalling pathway
What is vascular remodelling?
Alteration in radius of blood vessel and alteration in wall thickness of blood vessel
What does outward remodelling result in?
Increased diameter
What does inward remodelling result in?
Decreased diameter
When does remodelling take place?
Physiological conditions, high altitude, endurance training and pathophysiological conditions
Examples of physiological conditions?
Ageing, pregnancy
High altitude examples?
Acute hypoxia, cerebral and pulmonary oedema, prolonged hypoxia
What does endurance training change?
Conduit vessels have larger diameter, increase in number/density of arterioles (remodelling of capillaries driven by increase shear stress), capillary angiogenesis (VEGF) and increased mitochondria in muscle cells
What VEGF?
Vascular endothelial growth factor
Why could there be remodelling of vascular smooth muscle cells?
Responses to prolonged stimulation or pathophysiological insults
What is the shift from a contractile to synthetic phenotype in smooth muscle cells associated with?
Reduction in myosin expression and molecular and functional alterations in ca2+ signalling
What are examples of molecular and functional alterations in ca2+ signalling?
A move from L type to T type channel ca2+ entry, increasing involvement of TRP proteins in ca2+ cycling and switch in caMK11 isoforms
What happens to vascular smooth muscle in response to injury?
It undergoes a phenotypic switch, a process that contributes to pathophysiological vascular wall remodelling
