BIOM3020 Lecture Notes - Lecture 1: Blood Vessel, Perfusion, Vascular Resistance
Cardiovascular System
- The issue is the whole world is getting bigger
o In every country
o Pathologies related increase
o Also increases in medicine
▪ E.g. We have drugs which lower blood pressure
▪ Aging population
- Blood Pressure
o Important for Tissue Perfusion, flexibility and multiple systems
▪ Particularly brain – to get oxygen and nutrients
▪ As do most of the other tissues
▪ Kidneys – electrolyte balance
▪ Heart – heart has to beat rhythmically and push blood
▪ All systems run under pressure to maintain tissue perfusion
o Not static
▪ Constantly changing – depending on circumstance
▪ If blood pressure spikes too high it is a major risk for stroke and or heart attack
• BP increases in the morning
• Older people with CV most likely to die during morning
o 3 ways to increase blood pressure
▪ Ymapthetic drive coming from the brain to the heart and when you stimulate the heart starts beating faster and stronger to push
out more blood increasing BP
▪ Decrease diameter of key blood vessels to increase flow
• Increase peripheral resistance -> increased flow - > increased BP
▪ Increase retention of water/salt to increase blood volume
• Retain salt in the kiindey
• Retain water
• Increase blood volume
• Increase blood pressure
o When did we start measuring Blood Pressure
▪ Steven Hales
• Priest
• Went to the abotoire – cut the throat of horses the blood would shoot out
• Thought that that must be under pressure and how might I measure pressure
• Put a tube on the neck of the horse
o Blood goes up to a certain level
o Pressure pushes mercury up to a point
o High Blood Pressure
▪ Guidelines
• Systoli 120/80 = normal
• Prehypertensive 120/140
• High blood pressure stage1 140/150
• Highblood pressure stage 2 160+
• Hypertensive +180
o Last 4 are the people who start to get medication
o Prehypertensive – family history is also taken into account
o Look at weight, how much you smoke, how much you drink, diet
▪ New Guideline
• Becoming more conservative
• People are going to get it anyway
• Now considered elevated with anything above 120/129
• Hypertension starts lower
o Need to start treating people
o As a population if you loer blood pressure – lower stroke – heart attack - atherscleorsis
▪ As you age blood pressure increases
• Increase weight
o Increased metabolic synrom
o Renin angiotensin system is turned on
o angII cause vessels to constrict
• lasticity of vessels changes
o stiff blood vessels
o primary determinant of BP going up
o Hypertension
▪ Can’t tell who has hypertension
• Bill Clinton
▪ Genetic fsctors contribute
• African American have a gene which predisposes them to hypertension
▪ Comes down to treatment
▪ early treatment
• sedative
• low salt diet
• sympathectomy/adrenalectomy
o cuts sympathetic nerve
o now now sympathetic drive to vessels
o major thing to do
o drastick
o take adreal gland out
▪ makes aldosterone
▪ thereby getting rid of it
• Antimalerial (pentaquine)
o Found through luck
o Major side effects which had nothing to do with blood pressure
▪ Hazards
• Untils the early 60s doctors believed you shouldn’t treat it
• Reason blood pressure ges up because body is responding to the need of tissue perfusion
o Not true
• Risk factor for heart disease – attack/stroke and end – organ damage
• Increases hypertension strertches vessles and they tear a little bit
• Whit blood cells come in and try to fix
o See it almost as an inflammatory response
o Macrophages come in bringing more
o High fats high blood pressure
o Damage
o Inflammatory response
o Atherscleosis
o If it blocks it causes attack or stroke
o Breaks at a point of constriction – where the pressure is highest – happens at aorta – most pressure from heart
▪ Place where it is going to split
- Diuretics
o Big break through
o Help excrete out salt – water goes with salt – decrease blood volume – decrease blood pressure
o Act on kidneys
▪ One idea – low salt diet
• Nearly impossible – don’t get diertary requirements
▪ Next idea – try to excrete salt
• Antibiotic sulphanilamide – causes acidification of urine and loss of salt In the urine
• People had lower blood pressure
• Urine is being acidified
o Enzyme is kindeys Caronic anydrase,
o Sulphanilamide inhibited carbonic anhydrase
o Developed chlorothiazide
▪ Telling the kidney to not retain salt and with salt goes water
▪ Diuretic effect
▪ Still a very good drug for hypertension
▪ Decreasing blood pressure decreases rosk of one third of having stroke, myocardial infacotion and renal
damage
▪ Side effects
• Starts to change how body handles glucose and lipids
- Beta and Calcium Channel Blockers
o Cardiovascular disease cause angina (pain of chest)/how to treat
▪ One way you could do that would be to take the load off the heart
▪ Poor CV function
▪ Walking up steps
▪ Heart will start to spring for oxygen ecuase they have narrow vessles leads to angina in the heart
▪ Leading to angina
• Activating adrenaline
• Heart beats harder and stronger which deprives it of oxygen and you get pain
o IDEA
o Can we block adrenaline affect on the heart and will this decrease angina
o There are two types of adrenergic receptors
▪ Beta receptors in the heart and alpha receptors in the blood vessels
▪ Small molecule inhibitors (propranolol selectively bloc the bet receptors
▪ Relieves angina
▪ Byproduct – lower blood pressure
o Next dug to come
▪ Verapamil
▪ Has nothing to do with adrenalin
▪ Blocks entry of calcium into cells by clocking channels
▪ Need calcium to contract muscle
▪ Inhibitor of calcium entry relqaxaes blod vessels and a decrease in blood pressure
o Still has side effects
o Also tend to become resistance
▪ Body rsponds to get back to the stage it was before
▪ Resistant hypertension
- Discovery of Renin
o Took guinea pigs and took their testis out ground them up and injected into himself
o Idea was something was in the testicles which gives men their vigour
o What if you take a kidney and make an extract and inject it into another animal
▪ Something in the kidney is regulating blood pressure
▪ Profound increases in blood pressure
o Is that coming from the kindey
▪ Took blood out of renal vein leaving the kidney back intp rabbit with no kidney
• Changed the blood pressure
• Came from the kidney so called renin (fundamental discovery)
o People with hypertension had constriction of renal artery
▪ Is it the hypertension which causes the narrowing or the narrowing which causes the hypertension
▪ Constricts renal artery and see hat happens to hypertension
▪ Kidney clamp
• Simulated closing of renal artery
• Increases blood pressure
• Model of hypertension
• Prefent perfusion to the kidney and the kidney responds – suspected renin released from kindey increasing blood pressure
o Purificantion of kidney extracts to get a renin extraction
▪ The more pure it was the less activity it had
▪ Maybe something else is required
▪ Plasma added back in
▪ Increase in blood pressure
o Renin acted on a thing called renin –activator
▪ Purifies an activity called angiotonin or hypertensin
▪ Renin was an enzyme acting on agiotensin
- Discovery of ACE
o People started looking for angiotensin and trying to purify
o Everyttime they purified it came out as two bits
▪ AngI and AngII
▪ AngI wasn’t as active
▪ Started thinking you needed to convert AngI to AngII
o Renin cuts angiotensinogen to make AngI
o AngI is cut by ACE (ANGIOTENSIN convertin enzyme) to make AngII
o People were still sceptical
▪ Thought the real actitiy was from the adrenal gands – aldosterone
o Angiotensin works by activating the adrenal gland to release aldosterone
- Renin-Angiotensin-Aldosterone System (RAAS)
o Liver releases angiotensinogen and released into the blood
o Renin is released from the kidney in situations of low blood pressure
o Angiotensinogen is clipped to make angiotensin I by Renin
o ACE is sitting on blood vessels and clips Angiotensin I to Angiotensin II
▪ Particularly on lungs/high concentration
o Angiotensin II causes
▪ Acts on two different receptors ATR1 and ATR2
▪ Blood vessels to constrict
▪ Goes to brain and raises BP in brain/also makes you thirsty
o This is the blood born system
▪ But there are individual local systems as well
- Drugs for the system
o People were bitten by a pit viper and farmers were collapsing because their blood pressure was decreasing too much
o Put a vial (enough venom to kill 100 people)
▪ Causes blood pressure to drop
▪ Worked on the Angiotensin
▪ Found the venom had ihbitory activity on ACE – drug lead
▪ Extractewd the venom – it was a peptide
▪ Drug peptides need to be infused – can’t be taken orally
▪ Modelled it on another peptide
▪ Discovered captopril
• ACE inhibitor
• Saved millions of lives
- Angiotensin receptors
o Also have blockers of Ang Receptor
o Discovered AngI and AngII
o Which part of AngII is important
▪ When they made changes they changed the ability of peptide to activate a blood vessel therefore there had to be a receptor which
mediated binding and the changes that occurred
▪ First found to inhbit receptors was Losartan (anything with sartan at the end)
