S2: Circulation: Endothelium Flashcards
What are endo-VSM connections?
Direct connections between VSM and endothelium where electrical activity can pass through
What is EDRF?
Give examples
- Endothelium-derived relaxing factor (EDRF) is produced and released by the endothelium to promote smooth muscle relaxation.
- NO
- PGI2
What is EDHF?
- Endothelium-Derived Hyperpolarizing FactororEDHFis proposed to be a substance and/or electrical signal that is generated or synthesized in and released from theendothelium; its action is to hyperpolarisevascularsmooth muscle cells, causing these cells to relax, thus allowing the blood vessel to expand in diameter.
- K+
What part of the vessel wall do nerve innervate?
The adventitia
What are vasodilator nerves? List 3 of them
Vasodilation occurs as vascular tone produced by sympathetic vasoconstrictor nerves is inhibited.
- Parasympathetic vasodilator nerves
- Sympathetic vasodilator nerves
- Sensory (nociceptive C fibres) vasodilator nerves
Examples of parasympathetic vasodilator nerves innervating specific tissues with specific functions
- Salivary glands - release Ach/VIP
- Pancreas and Intestinal mucosa - release VIP
Both these tissue need high blood flow to maintain fluid secretion e.g. saliva. This is why we have dry saliva during excersize as blood flow is diverted elsewhere. Ach/VIP act on the endothelium to cause release of NO which then causes vasodilation.
- Male genitalia (erectile tissue) -release NO
Release of NO by parasympathetic nerves causes production of cGMP leads to vasodilation.
How does sildenafil (viagra) work?
Sildenafil (Viagra) enhances the effect of NO by blocking the breakdown of cGMP by phosophodiesterase 5
Describe sympathetic vasodilator nerves in skin
- Skin (sudomotor fibres) - release Ach, VIP (sweat)
This is vasodilation associated with sweating. This makes sense as when it is hot more sweat needs more blood flow to the skin to cool down. Sympathetic vasoconstriction would only reduce blood flow limit sweat production to limit cooling down.
Head, face, upper chest, involved in blushing would still heat individual. This is a stress (sympathetic) response
Describe sensory (nociceptive C fibres) vasodilator fibres
How does it produce ‘flare’?
- Stimulation of sensory axon reflex (C fibres) by trauma, infection etc. to spinal cord and this is perceived as pain
The impulse is also conducted to axon collaterals which releases Sub P, CGRP which:
- Act on Mast cells to release histamine which then act on blood vessels
- Act on endothelium and VSM
Both produce vasodilation called ‘flare’ in the skin. The local dilation is seen as redness due to increase in blood flow which brings in immune cells and rids toxins.
List some endothelium derived relaxation factors
- Nitric Oxide (NO)
- Prostacyclin (PGI2)
How is NO released, synthesised and how does it produce vasodilation?
These factors drive the production of eNOS and subsequently NO:
- Shear stress from blood flow (friction flow and wall) - this causes constant release of NO
- Inflammatory factors (Sub P, histamine, BL), Ach
Endothelium nitric oxide synthase (eNOS) produces NO in endothelium cells from amino acids.
Mechanism of NO:
- NO diffuses out of endothelium cell down its conc gradient into VSMC
- NO is positively associated with GC
- GMP is converted to cGMP
- cGMP is converted into PKG
- PKG causes vasodilation
What is Nitric Oxide?
- Lipophilic soluble gas
- Freely diffusible
- Stimulates GC to produce vasodilation
How is PGI2 released, produced and how does it produce vasodilation?
Factors stimulate receptors on endothelium: e.g. shear stress, inflammatory factors and Ach
- Membrane lipids turned into PGI2 by COX
- PGI2 binds to PGI2 receptor (prostanoid receptor) on smooth muscle
- Gs pathway stimulated producing PKA
- Vasodilation occurs
Why is PGI2 important in the kidney?
This is important in the kidney because vasodilatation increases blood flow to glomerulus to keep glomerular filtration rate high
- Tonic PGI2 production is important in maintaining blood flow in renal arterioles
- Needed to maintain GFR and kidney function- COX inhibition (NSAIDs) are potentially dangerous in kidney failure
- Also, important pathway in inflammation mediated vasoconstriction
How do PKA and PKG (produced by NO and PGI2) produce vasodilation?
PKG and PKA in vascular smooth muscle cells phosphorylase:
- Ca ATPase (SERCA) - increase uptake into SR stores and exclusion from cell (SERCA found on SR and cell membrane). This leads to less calcium rise inside the cell decreasing contraction and increasing relaxation.
- K+ channel activity so K+ leaks out of the cell more. This causes hyperpolarisation in the cell which switches off VGCCs.
- Decrease in MLCK enzyme which decreases phosphorylation of MLC.· All these actions in reduce Ca2+ levels and reduce action of contractile mechanisms
Name a endothelium derived hyperpolarisation factor
K+
How is K+ released, produces and how does it produce vasodilation?
Stimulated by: E.g. shear stress from blood flow , Inflammatory factors (Sub P, histamine, BK), Ach
These stimulate receptors which activate K+ channels in the endothelium so K+ moves out of the cell down its concentration gradient.
This causes:
- Rise in localised external K+ concentration which acts on vascular smooth muscle cells and switches on K+ channels
- Increases Na/K-ATPase which moves K+ inside muscle cell (2K+ for 3Na+ outside cell). Overall decrease of potential in cell as more positive charges are leaving.
This leads to hyperpolarisation of VSMCs decreasing VGCCs and Ca2+ entry producing vasodilation.
What is endothelium derived hyperpolarisation?
Factors stimulate K+ to leave e.g. Shear stress from blood flow, Inflammatory factors (Sub P, histamine, BK), Ach
- Endothelium becomes hyperpolarised as they lose K+. They are non excitable cells but their membrane potentials can be depolarised and repolarised.
- Conduction of hyperpolarisation from endothelium to VSMCs through gap junctions
- Hyperpolarisation in VSMCs decrease VGCCs and Ca2+ entry
- Vasodilation
What balance causes the end result of vascular tone?
Balance between the two effects: Vasoconstrictors (e.g. NA) of VSMCs and vasodilators of endothelium that causes the end result of vascular tone
What is a gap junction?
Connexin proteins - big pores that allow communication and they are a low resistance, highly conductive pathway
Explain how stimulation of b2-adrenoceptors on VSMCs produces vasodilatation in coronary and skeletal muscle arteriole
B2 adrenoreceptor stimulation by adrenaline activates Gs pathway so PKA is made causing vasodilation by:
- Increasing Ca ATPase (SERCA) - increase uptake into SR and exclusion from cell
- Increase K+ channel activity causing hyperpolarisation decreasing VGCCs
- Decrease MLCK
- Important for increasing blood flow to heart and skeletal muscle during exercise
- During excersize, there is a lot of sympathetic nerve activity (e.g. Increase CO -> increase BF)
- Increase BF needs to reach heart and skeletal muscle, adrenaline helps selectively increase BF to certain parts of the body
What are the functions of the endothelium?
- Vascular tone
- Blood-tissue interactions e.g. Production of Ang II occurs because endothelium surface contains Ang II converting enzymes in the lungs.
- Blood clotting, Inflammatory pathway, Angiogenesis, Atheroma
Describe endothelial dysfunction (what breaks it down, what is it linked to)
Breakdown of endothelium function e.g. hypertension, diabetes, cigarette smoking has profound action on vascular tone e.g. reduce NO/PGI2 production, enhance vasoconstriction
Hence ED is linked to many CVD
Also, explains why systemic infection/inflammatory (e.g. Sepsis) leads to activation of so many different vasodilator pathways and is very difficult to treat due to all the different factors released by endothelium
