What is vasodilation?
Relaxation of the vascular smooth muscle (vascular - associated with blood)
What is the structure of a blood vessel?
- Tube (lumen) surrounded by smooth layer of muscle
- Inside of blood vessel has a layer of endothelium
What is angina?
- Plaque in blood vessels of the heart, and so unable to get enough oxygen to the muscles of the heart and so cannot relax properly
- Results in chest pain
- Important cause of cardiovascular death
How did Robert Furchgott investigate vasodilation?
- Tension device connected to ring of aorta from rabbit in organ bath
- Contract first with noradrenaline and then adding acetylcholine to see relaxation
What results did Furchgott obtain?
- Non reproducible results
- Either a steep decrease in tension with acetylcholine or high tension until very high conc of acetylcholine
What was the cause of Furgott’s results?
- Student accidentally removing endothelium from aorta
- Therefore Ach was not acting directly on muscles but on endothelium, idea introduced of endothelium derived relaxing factor (EDRF)
What evidence was supplied by Ignarro and Salvador Moncada that NO was EDRF?
- Small molecule that can diffuse quickly
- Can activate guanylate cyclase as free radical binds stongly to Fe in haem group of molecule
What is the proposed mechanism of vasodilation?
- Arrival of Ach causes Ca2+ channel to open
- Ca2+ activates NO synthase which acts upon Arganine and Oxygen to produce citrulline and nitric oxide
- Nitric oxide binds to guanylate clyclase activating it
- Conversion of GTP to cGMP which acts as a protein kinase inducing relaxation
Why is the synthesis of NO through arganine unlinkely?
Uses oxygen, vasodilation used to deliver more oxygen to tissue
What is an alternative explanation for the source of NO? What evidence exists of this?
(NO2-) (nitrite) -> NO
- Always present in blood plasma, conversion not difficult to effect
- Fall in nitrite content between arteries and veins (however very little)
- Higher concs of nitrite in Tibetan highlanders (stronger evidence but still not entirely proven)
What alternative explanation exists for the synthesis of NO aside from NO2-?
S-nitothiols (formula RSNO) decompose 2 RSNO -> RSSR +2NO
S-nitrocysteine and S-nitrogulathione circulate in the blood
What did Jonathan Stamler propose the mechanism for NO?
Nitric oxide carried by haemoglobin in the cysteine residue (conserved in many species with no obvious use) to give SNOHb
However:
Probably not correct as rat with induced human haemoglobin without cysteine residue shows no fatigue effects
How is NO involved with blood clotting?
Prevents platelet aggregation and cohesion (procued by eNOS)
What is the involvement of NO in the immune system?
- Found that participants who have had fevers have high ammounts of nitrate in their urine
- NO reacts with superoxide in lysosome to for peroxynitrate which is then converted to nitrate and excreted
What is the role of NO in respiration?
- Nitric oxide binds to Fe4S4 clusters ending respiration and leading to necrosis
What is the role of NO in the brain?
- Glutamate is the neurotransmitter
- Binds to NMDA receptor
- Opens channels to allow calcium ions to flow into the postsynaptic neurone
- Stimulates nNOS to convert arginine into NO
- NO diffuses back, reaching not only presynaptic neurone but many others, mechanism in memory could decay with age?
What is the role of nitric oxide in the peripheral nervous system?
- NANC nerves (non-adrenergic non-cholinergic) have NO as their transmitter
What are the properties of H2S?
- Extremely toxic
- Bad odour
- At physiological pH present a the hydrogen sulphide ion (Hs- + H+)
- Obtained from cysteine by 3 enzyme: CBS, CSE and 3-MST and is also manufactured by intestinal flora
- Reacts with another HS group to form S-S bond (sulfhydration)
What are the roles of H2S in the cardiovascular system?
- CSE knockout mice show hypertension and impaired vasodilation
- Enhances Katp channels
- Disregulated H2S biosynthesis associated with maternal hypertension and pre-eclampsia
What is the role of H2S in the gut?
CBS, CSE and 3-MST manufactured by resident microbes
Role in smooth muscle relaxation, protection against inflammation, damage and alcohol induced gastritis
Where is H2S found in the nervous system?
- CBS found in the glia
- CSE and 3-MST found in neurons
Multiple sources indicate importance
What is the proposed role of H2S in the nervous system?
- Long term potentiation likely involves sulfhydration
- Disregulation of H2S metabolism occurs in Alzheimers and Parkinsons
How are H2S and NO synergistic?
- In aorta low concentrations of H2S greatly augments NO induced smooth muscle relaxation
- Reducing CSE activity reduces response of NO donors and vica versa
- Vasodilatory effect of H2S is lost in eNOS knockout mice
Give an example of H2S and NO direct chemical reaction
- Enzymes producing these compounds are co-located
- H2S can react with nitrosothiol to give HSNO (thionitrous acid the simplest and first nitrosothiol, possible vasodilator) however this degrades at 12K so probably not
- HSNO does ionise however to give H+ and -SNO
