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191 Cards in this Set
- Front
- Back
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What is the structure of a lipoprotein?
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They are small particles with coat and a core
The coat = phospholipids, cholesterol and proteins (apoproteins) Core = cholesterol esters and triglycerides |
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With atherosclerotic plaques, are the bigger or smaller lesions generally more problematic?
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The smaller ones because they're faster growing
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What does the body use TAGs for?
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They're a source of fatty acids which the tissues use for energy
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What does the body use cholesterol for?
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Synthesis of steroid hormones, bile salts and used in plasma membranes
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How do we transport cholesterol and TAGs around the body?
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In lipoprotein particles
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What do the lowest density lipoprotein particles contain?
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the lowest density ones are richest in TAGs
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What do the highest density lipoprotein particles contain?
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Cholesterol esters
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What is the role of LDL particles in the body?
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The deliver cholesterol to the cells that need it
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What is the role of HDL particles in the body?
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They remove cholesterol from cells that have too much (reverse cholesterol transport)
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How are LDL particles produced?
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We get VLDLs produced in the liver - they contain mostly TAGs (but some chol as well). They go around the body and get metabolised -> TAGs provide fatty acids for energy
As the VLDL is drained of its TAGs, it also loses all of its apoproteins except apoB100 Eventually, we're left with an LDL - only has cholesterol esters inside and the only protein is apoB100 |
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How do cells signal that they need cholesterol?
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They upregulate their expression of the LDL receptor -> will bind apoB100 on the LDL particles
The reverse is also true, when cells have enough chol, they downregulate LDL R expression |
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What is the role of apoB100?
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It's a protein on the surface of teh LDL particles. (each LDL has only one apoB100)
It binds to LDL Rs on cells that need cholesterol |
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How do we get the formation of foam cells? ie if there's such a good feedback loop controlling cholesterol delivery to cells, how do we get so much in one cell?
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The apoB100 molecule gets modified by covalent addition (glycosylation and/or oxidation often on lysin residue) -> it now looks different and will no longer bind to the LDL R on the cells. Instead, it gets picked up by the scavenger receptor on macrophages --> bind in an unregulated and uncontrolled fashion
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Why do LDL particles become 'atherogenic' in the plaques?
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We have inflammation going on -> lots of ROS are generated. Some of these can result in the apoB100 on the LDLs getting oxidised -> the apoB100 will now look different -> no longer binds the LDL R in regulated manner, instead gets taken up by the scavenger receptor on macrophages
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What are statins?
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HMG CoA reductase inhibitors?
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What drugs do we use to lower cholesterol? How do they work?
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Statins ie they inhibit the HMG CoA reductase enzyme -> we don't convert HMG CoA to mevalonate. This is a crucial step early on in the synthesis of cholesterol
Additionally, as a result of decreased chol synthesis, hepatocytes increase their expression of LDL Rs (trying to grab any LDLs they can) --> further decrease circulating LDL levels |
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What are the three effects of statins?
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Decreased synthesis of cholesterol (this is the main effect)
Increased LDL clearance (upregulation of receptors on hepatocytes) Moderate increase in HDL levels (we don't know why) |
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What is normal LDL level?
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3mM
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What happens in familial hypercholesterolemia?
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Have disturbed LDL R function
Maybe it doesn't properly bind the LDL or if it does bind the particle, doesn't internalise it properly |
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What pattern of inheritance do we have with familial hypercholesterolemia?
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Autosomal dominant
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What is the role of HMG CoA reductase?
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It converts HMG CoA to mevalonate = crucial early step in cholesterol synthesis pathway
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What is the effect of statins in someone with familial hypercholesterolemia?
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Heteros have one good and one bad LDL R.
The statins promote expression of the good receptor in these people -> cells that need LDLs can bind and internalise them -> we get less LDLs in circulation |
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Where is apoB1 found?
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On the surface of HDL particles
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Where is apoB100 found?
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Surface of LDL particles
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What is the role of apoB1?
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It's on HDL particles. Binds to a receptor on a cell that has accumulated cholesterol
Also involved in activating the enzyme LCAT (lecithin cholesterol acyl transferase) |
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What is LCAT and what does it do?
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Enzyme that transfers a fatty acid from a lecithin (phospholipid) molecule in the HDL particle's coat to a cholesterol molecule that's inside the cell (HDL has docked on a cell that wants to get rid of its excess cholesterol) -> now we have a cholesterol ester which can move into the core of the HDL particle
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What's the process of reverse cholesterol transport?
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HDL docks on the cell - mediated by apoB1 binding to R that's been upregulated on that cell
ApoB1 then activates the enzyme LCAT -> we transfer fatty acid from a phospholipid in the coat of the HDL (lecithin) to one of the cholesterol molecules in the cell -> now we have a cholesterol ester which can go into the core of the cell This process continues until we run out of lecithin molecules in the HDL coat |
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What does an HDL particle do with all its cholesterol when it's just been filled up?
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Interacts with VLDL remnant -> HDL gives its cholesterol to it and the VLDL remnant then becomes an LDL particle
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Do high or low levels of TAGs promote atherosclerosis?
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HIgh levels promote atherosclerosis
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What are fibrates?
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Drugs that lower TAG levels (by increasing the catabolism of TAGs) -> reduce atherogenecity
They also suppress VDLD production in the liver -> decreased LDLs |
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What's bad about TAGs in terms of atherosclerosis etc?
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- They lower HDL levels
- Make LDLs more atherogenic - They're in high conc in VLDLs( which cause artery damage) W |
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What causes ST elevation?
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Transmural ischaemia
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What causes ST depression?
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Subendocardial ishaemia
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Is ST elevation usually a demand or a supply ischaemia?
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Supply
The ischaemia has gone through the whole wall - probably because we've had occlusion of a major coronary vessel |
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Is ST depression usually a demand or supply ischaemia?
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Demand
It's just subendocardial ischamia - there's probably some lumen narrowing but increased demand has brought on the ischaemia |
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What more longterm changes do we get in an ECG after ischaemia?
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T wave inversion (not permanent, goes back after a few months)
Pathological Q wave (due to dead myocardium - won't return to normal) |
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What are the criteria for a pathological Q wave?
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It's wider than one small box
and height is greater than 25% of the total QRS complex |
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Do we get pathological Q waves with both STEMIs and non STEMIs?
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No only with stemis - need a transmural infarction
It's the big chunk of dead tissue that's causing the path q wave in the lead/s overlying the area |
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Will you always get a pathological Q wave with an acute STEMI?
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NO
ST elevation shows there's ISCHAEMIA but we don't yet have permanent tissue damage If we reperfuse the area in time, we will not have infarcted tissue -> don't get a Q-wave |
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What is ST elevation more accurately referring to on the ECG?
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QT depression
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What is ST depression more accurately referring to on the ECG?
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QT elevation
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Which ECG leads look at the inferior wall?
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II III aVF
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Which ECG leads look at the lateral wall?
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v6 and aVL
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Which ECG leads would show changes if we had LAD blockage
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looking at anterior heart
ie V1-5 |
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Which ECG leads would show changes if we had blockage in the right coronary artery?
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Right coronary supplies inferior wall -> looking at II III and avF
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Which ECG leads would show changes if we had blockage of left circumflex artery?
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left circum supplies lateral wall -> would see changes in V6 and aVL
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What happens to conc of H+ after ischaemia?
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Decreased O2 -> switch from fatty acid oxidation to anaerobic glycolysis -> lactic acid produced ie lower pH / increased conc H+
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What happens to EC conc of K+ after ischaemia?
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Increased
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Which medications could interfere with the usefulness of exercise stress testing?
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beta blockers and certain Ca2+ channel blockers
This is because they slow a person's HR -> won't reach their target HR - can mask the changes we're looking for |
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In an exercise stress test, who has higher rate of false positives: men or women?
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Women
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With exercise stress testing, what is a positive response? (3 things)
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- angina
- ST segment depression - fall in BP or failure to rise |
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What do we do in nuclear perfusion scanning?
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Inject radionucleotide-mibi complex (usually use Tc99m as our radionucleotide) (ie sestamibi)
It will accumulate in the heart in proportion to the degree of perfusion of viable myocardial cells We use gamma camera to detect the gamma rays coming out Do it before exercise (rest) and immediately after -> compare the two images, looking for cool areas during exercise which would suggest that we have demand ischaemia happening in those areas |
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If we can't get someone to exercise for our stress tests, what do we do?
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Give them dobutamine = synthetic analogue of dopamine -> acts on the beta1 receptors -> increased heart rate and force of contraction
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What sorts of things can we see with an echo?
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- Ventriular function
- Valvular function - Dynamic assessment of wall motion |
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What is coronary calcium scoring with electron beam CTs?
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We look at the amount of calcification in the coronary vessels
-> we're using ca2+ as a surrogate marker for plaques. |
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What are the disadvantages / problems with coronary calcium scoring with CT?
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We're using Ca2+ as surrogate marker for plaques. Problems include:
- plaques with high Ca2+ are often not the ones we need to worry about (probably means they're pretty stable) - doesn't give us info on how obstructed the lumen is |
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What is the best technique for identifying coronary artery stenoses?
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Angiography
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Disadvs of angiographY?
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- invasive, risk of bleeds, needs local and contrast agents, risk of infection, risk of stroke,
- can only be done in specialist centres - doesn't give us info about composition of plaque / its vulnerability - shows us how narrow the artery is but this isn't directly related to clinical significance |
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What is the 'sensitivity' of a test?
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The capability of the test to pick up those with the disease / problem
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What's the selectivity of a test?
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The capability of the test to recognise normal subjects
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Which medications do we use to alleviate symptoms of angina?
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Nitrates
beta blockers ca2+ ch blockers |
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Which medications do we use to improve prognosis of someone with ischaemic heart disease?
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Aspirin
Beta blockers Statins ACE Is |
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What are the modifiable risk factors for ischaemic heart disease?
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- high chol
- smoking - diabetes - obesity - hypertension |
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For each modifiable risk factor of IHD that you have, what happens to your risk of a cardiac event in next 10 years?
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Each risk you have doubles risk
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What are the determinants of myocardial O2 demand?
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- HR
- Contractility - Wall stress (LV dimension x afterload) |
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What happens to coronary blood flow with tachycardia?
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Decreases
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What do nitrates do?
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They relax vascular smooth muscle via NO and cGMP mechanisms - vaso and veno dilation
-> decreased afterload and decreased preload |
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How are the short acting nitrates administered?
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Sublingual tablets or oral spray -> absorbed from the oral mucosa
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What is the problem with the longer acting nitrates?
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you develop tolerance to them within 24 hours -> need to have a 10 hour period without them in your system to avoid this
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What SEs do you get from nitrates?
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Headaches (due to the vasodilation)
Also could faint due to the hypotension - should be siting when they take their spray |
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How do beta blockers have an anit-anginal effect?
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They decrease HR and contractility and hence they reduce myocardial O2 demand
Also, slow HR -> increased time in diastole -> more time for blood to be supplied to the heart |
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What do we have to be aware of when using beta blockers?
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Though they're meant to be beta 1 selective, might have some effect on beta 2 - need to be careful with asthmatics / COPD and people with peripheral vascular disease
Also, need to be careful with the non-dihydropyridine Ca2+ blockers -both decreased HR and contractility -> could get dangerously low if you use them together Also careful with diabetics - can mask the tachycardia and other catecholamine mediated responses that warn a diabetic that they're hypoglycemic |
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What SEs do we get with beta blockers?
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fatigue
loss of libido, impotence sleep problems / bad dreams need to be careful with asthmatics, COPD, peripheral vascular disease and diabetics |
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What channel do calcium channel blockers work on?
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voltage gated L type calcium channels
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What is the effect of all the calcium channel blockers?
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Arterial vasodilation -> decreased afterload -> decreased work of the heart
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What are the two groups of Ca2+ channel blockers?
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1. Non dihydropyridines - in addition to causing vasodilation, these are potent cardiac depressants
eg verapamil and diltiazem 2. Dihydropyridines - only act on vascular smooth muscle cells Nifedipine and amlodipine |
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What is diltiazem?
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Ca2+ channel blocker
One of the ones that depresses cardiac function (decreased HR and contractility) as well as the normal vasodilation |
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What is ivabradine?
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blocks funny current in SAN -> slows HR
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What is perhexiline
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inhibits some crazy enzyme -> reduced requirement for aerobic metabolism by the myocardium
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What is our fave drug to give people with ischaemic heart disease to improve their prognosis? becuase it's so simple cheap and effective?
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ASPIRIN
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S/Es of aspirin
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GIT problems
intracranial haemorrhage asthma provocation allergies |
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What drug do we give to all people with coronary artery disease to continue indefinitely?
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aspirin
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what is clopidogrel?
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Blocks the ADP receptor on platelets -> prevents platelet aggregation and activation
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When do we use the clopidogrel + aspirin combo?
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In people who've just had a stent put in
People for whom aspirin prevention alone wasn't enough |
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What treatment do we have to give after putting in an a) normal and b) drug eluting stent?
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Normal - will have endo cells grown over in a month - for this month need clopidogrel + aspirin combo treatment (the stent is hugely thrombogenic till its covered in endo cells)
Drug eluting stent - takes way longer (12 months) for endo cells to grow over -> continue this double treatment for the whole year |
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what do we give someone who's just had a drug eluting stent put in? and for how long?
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give them clopidogrel and aspirin combo treatment for 12 months
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T/F: clopidogrel is a prodrug?
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True
Some people might not oxidise it very well into its active form |
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Can we dissolve the cholesterol in plaques with statins?
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no
But prevent the plaques from getting bigger / at least slow the process |
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Healthy diet alone will decrease your circulating LDL levels by approx how much?
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10-15%
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Statins will decrease your circulating LDL levels by how much?
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About 30%
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What are some of the SEs with statins?
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myalgia
raised CK levels potential impacts on hepatic function |
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Do all statins have the same SE profiles?
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no
all statins vary quite a lot (in efficacy and s/es) |
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Why do we give statins to people with coronary artery disease?
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Slows progression of the plaques we already have -> decrease risk of future cardiac events and improve your prognosis
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Do statins improve your prognosis if you have coronary artery disease?
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yes
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Do nitrates improve your prognosis if you have coronary artery disease?
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no
they just give symptom relief (angina) |
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Do beta blockers improve your prognosis if you have coronary artery disease?
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They definitely give symptom relief
And in some people they do improve prognosis |
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Why do we use ACE Is in coronary artery disease?
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They improve your outcome and survival (decreased afterload)
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What are the side effects of ACE Is?
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dry cough
angioedema hypotension renal problems can't use in pregnancy |
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What groups of people with coronary artery disease would we revascularise?
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- their symptoms aren't controlled with drugs alone
- they have too many side effects with drugs - their blockage is known to respond particularly well to revascularisation eg left main artery stenosis |
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What are the two most common BVs used in bypass surgery? Which has best patency in 10 years time?
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Saphenous vein
Internal mammary artery (best patency 10 years later) |
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What is coronary angioplasty?
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We go in through a peripheral artery (femoral, brachial or radial) with a balloon tipped catheter) and get up to the stenoses vessel
We inflate the balloon to dilate the stenosis -> bigger lumen and hence better blood flow |
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What are the two types of stents we can use ?
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Bare metal stent - will be covered with endo cells after a month
Drug eluting - decreased chance of restenosis but there's a delay in covering with endo cells -> need to be on combo anticoagulation for 12 months |
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What causes intermittent claudication?
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Exercise -> increased flow demands - artery is too blocked to be able to meet the increased demands -> ischaemia -> build up of metabolites and H+ -> pain
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If we measure the perfusion pressure distal to a blocked leg artery, what happens over time?
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pressure will usually increase with time because they have collateral vessels forming
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What are the three layers of an artery?
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Intima
Media Aventitia |
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What is in the intima of a muscular artery?
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Endo cells
+ internal elastic membrane |
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What's in the media of a muscular artery?
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Lots of smooth muscle cells
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What's in the adventitia of a muscular artery?
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Loose connective tissue + fibroblasts
The external elastic membrane |
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What is the first step in atherogenesis?
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Endothelial damage (this is due to the various risk factors)
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When endothelium gets damaged, what happens to it?
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We've lost the normal protective mechanisms (eg NO production, anti-platelet molecules and anti-inflamm substances)
It's activated -> increased expression of adhesion molecules (eg VCAM-1), production of cytokines etc (recruit more cells into the area) and increased permeability |
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What happens during inflammation to the LDL particles?
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They get oxidised due to presence of all the ROS
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What is a fatty streak?
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The early atherosclerotic lesion. COntains foam cells adn some T-cells
It's not significantly raised, doesn't disturb blood flow. Just yellow spots on inside of the artery. They're present in aorta and coronary arteries of most people by the age of 20 |
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By what age are we able to detect fatty streaks in people's aorta and coronary arteries?
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By the age of about 20
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What do smooth muscle cells do during atherogenesis?
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The migrate out of the media and into the intima. -> intima increases in size -> lumen starts to narrow
They also change from being contractile to synthetic -> lots of proliferation in the intima |
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What is the fibrous cap in a plaque made of?
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The altered smooth muscle cells, collagen and proteoglycans
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What are the three possible consequences of a plaque rupturing?
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1. Can cause a thrombus that blocks the vessel -> ischaemia then infarction
2. Can get intra plaque haemorrhage ->increased occlusion but not totally blocked 3. Necrotic core escapes and travels as an atheroembolus - can occlude distal BVs |
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What are the non-modifiable risk factors for atherosclerosis?
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- age (increased risk with increased age)
- male sex (pre-menopausal women have estrogen -> increased HDL levels and improved endothelial function. Once women are past menopause, we don't see this protective effect anymore) - Genetics (huge genetic involvement) |
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Why are women at lower risk of atherosclerosis than men?
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This is only BEFORE menopause
Because of estrogen - it results in higher HDL levels and improved endothelial function |
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What are the 5 main (+1 rando) modifiable risk factors for atherosclerosis?
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- Hyperlipidaemia (lots of this is genetic, but also related to diet, exercise etc)
- Hypertension - Smoking - Diabetes (get glycosylation of the LDLs) - Hyperhomocysteinemia (because homocysteine causes increased oxidant stress, endo dysfunction and induction of thrombosis) - Infection - there's some suggestion that chlamydia and CMV infection in plaque may aggravate it, but this is controversial |
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Which an atheroma, which layer of the artery changes most in size?
What happens to external diameter? |
It's the intima that changes most
Outside diameter doesn't change much |
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Is atherogenesis associated with eccentric or concentric thickening?
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Eccentric ie it's off centre / not symmetrical
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In a slide of teh necrotic core of a plaque, what do we see?
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There are elongated cleft like spaces (where chol has ppted out) and then pink material around the clefts (dead cell debris)
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In the heart, how long do we have between cessation of flow and irreversible damage
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2-6 hours
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What sequellae do we see after an MI?
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- Cardiogenic shock
- Arrhythmias - Congestive cardiac failure - Fibrinous pericarditis - Mural thrombus - Rupture of external wall, IV septum, pap muscles - Anuerysm of the LV |
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What does the healthy endothelium release to maintain vascular tone?
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- prostacyclin (PGI2) = dilator
- endothelin = constrictor - NO = dilator |
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Is the composition of the atherogenic plaques the same throughout the body? What is it like in the aorta and in the coronary arteries?
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No
Aorta - more macrophages Coronary arteries - more smooth muscle cells |
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Do we have complement involved in atherogenesis?
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YES!
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If you already have a well developed plaque and you lower your cholesterol levels, will you improve your plaque?
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Not significantly
Might get a tiny bit of regression / changed composition but this is minor You will however get slower progression -> improved prognsosis and survival |
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What does LV wall stress depend on?
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LV volume and afterload
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What are the three major determinants of myocardial O2 consumption?
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Heart rate
LV wall stress Contractility |
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How much does blood flow increase during exercise?
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5 times
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How much does the coronary vessel lumen need to be occluded for us to get angina during exercise?
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70% occlusion -> demand ischaemia ie angina during exercise
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By what percentage does the coronary vessel lumen need to be occluded for us to get angina at rest?
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If it's 90% occluded, we have supply ischaemia ie angina at rest
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What is supply ischaemia?
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The vessel is so blocked that it's simply not able to supply enough O2 to the tissue even at rest
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What is demand ischaemia?
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The tissue has increased its O2 demand and the artery isn't able to meet this increased demand
But at rest, the tissue would be getting enough O2 |
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What happens in the first few seconds of ischaemia in the heart tissue?
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There's a switch from aerobic utilisation of fatty acids to anaerobic glycolysis -> production of lactic acid
Anaerobic glycosis isn't as efficient -> decreased production of ATP |
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What happens when we have anaerobic glycolysis in the heart due to ischaemia?
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PRoduciton of lactic acid
Decreased ATP production --> - decreased contraction and relaxation (they both require ATP!) - Na-K+ pump will slow down -> increased Na+ inside and increased K+ outside -> cell becomes slightly depoled-> AP is reduced in size and duration AND Na+-Ca2+ antiport is stuffed |
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what happens to Na+ conc in myocardial cells during ischaemia?
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Increased Na+ inside (because NaKATPase isn't working properly)
THis will: - slightly depol cell -> decrease size and duration of APs - NaCa2+ antiport is stuffed- increased ca2+ in cell -> impaired relaxation and they ca2+ activates proteases -> membrane damage and eventual cell death |
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What molecule is believed to be responsible for angina?
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ADENOSINE
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Sympathetic afferents leaving the heart synapse at which levels?
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C8-T4
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What happens in the early stage of peripheral vascular disease?
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We have demand ischaemia -> they get pain when exercising in the muscles supplied by the narrowed vessel
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As peripheral vascular disease progresses to serious disease, what symptoms do they have and why?
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They have pain at rest - this is due to ischaemia of teh peripheral nerves rather than the muscles
Might have altered sensation in feet and toes and/or burning numbness |
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What is the big risk of PVD?
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After minor trauma or infection, they might get ischaemic ulcers/ gangrene
(Decreased healing because of decreased flow) |
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In peripheral vascular disease, what is the most common location of occlusion?
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The femero-popliteal segment
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What's the ankle/brachial index and why do we calculate it?
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Comparing the pressures in ankle with those in the arm -> we're looking for peripheral vascular disease in the leg
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what are the three main tests we do when assessing peripheral vascular disease?
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- Continuous wave doppler (looks at the BPs as we move down the leg)
- Angiography - Arterial duplex scanning (we look at flow velocities) |
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What sort of characteristics are seen in someone with type A personality behaviour?
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hostility, insecurity, time urgency, impatience and competitiveness
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Is type A personality a robust predictor of coronary heart disease?
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NO
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Is type D personality a robust predictor of coronary heart disease?
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YES
It seems to be related to cardiovascular morbidity and mortality |
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What is type D personality?
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Negative affectivity
Social inhibition |
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Is psychological hardiness and resilience associated with positive health outcomes?
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Yes
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Is conscientiousness associated with positive health outcomes?
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Yes - they tend to lead healthier lives, be more compliant with medical care etc
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Why does MI increase risk of arrhythmias?
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Could be due to infarcts in conduction system -> brady arrhythmia
Infarcted tissue can become fibrotic and then promote re-entry circuits -> tachy arrhythmias |
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What is mural thrombosis and why is it a complication of MI?
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If we have infarction in the LV, there might be decreased ventricular wall movement -> can get static blood = predisposed to clotting -> mural thrombosis
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What happens to the heart wall after an infarction?
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Cardiac remodelling -> the area of infarction undergoes disproportionate stretching and thinning (also get some of this is the adjoining areas) --> Increased wall stress and decreased contractility
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How many people die prematurely each year from air pollution wordlwide?
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2 million
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Air pollution is responsible for what proportion of deaths in australia?
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2.3%
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is there a statistically significant link between particle levels (eg from soils, incinerators, motor vehicles, wood burning heatings, bush fires etc) in the air and CV problems?
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YES
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Why are high particle levels believed to be linked with CV disease? Two theories
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- They trigger systemic inflammation -> altered clotting chemistry and change in the stability of atheromatous plaques
- impacts on neural reflex -> arrhythmias |
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Why is carbon monoxide associated with CV disease?
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Increased carbon monoxide - decreased O2 binding to Hb -> the heart a) has to pump harder to meet the body's needs
and b) is more likely to be not getting enough O2 itself -> angina |
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What three air pollutant components are associated with CV disease?
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- particles
- CO - Lead |
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How is lead linked to CV disease?
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It causes hypertension
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why do branch points in the arteries have increased risk of atherogenesis?
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- high turbulence
- high endothelial turnover - high endothelium permeability |
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In which areas of the body do the BVs have dense sympathetic innervation?
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low priority organs (we'll switch off blood flow in fight or flight response)
eg skin, kidney, GIT |
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Which areas of they body is there low density of symp innervation to BVs?
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tissues that we don't want flow to change in fight or flight
brain and heart |
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Which is the lowest density lipoprotein?
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chylomicron
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What does PDGF dO?
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It's responsible for the change of smooth muscle cells from contractile to synthetic in the atherogenesis process
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In which BVs do we have the biggest drop in pressure?
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The arterioles -> they have the largest resistance
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What are the three extrinsic determinants of arteriolar smooth muscle constriction?
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- symp vasoconstrictor nerves
- vasodilator nerves - circulating hormones |
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Which receptors do sympathetic nerves act on in the vascular smooth muscle?
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ALPHA RECEPTORS
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What happens with NA binds to alpha receptors on vascular smooth muscle?
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Vasoconstriction
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Where in the body do we have parasymp innervation of BVs?
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In the GIT -> turned on for digestion
In the penis -> erection |
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What does parasymp innervation of a BV do? Do we have widespread parasymp innervation of BVs?
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Get vasodilation
Parasymp nerves don't innervate BVs all throughout the body - only in the GIT and penis |
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What happens when adrenaline binds to beta receptors in the coronary arteries?
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Vasodilation
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What's ADH's impact on BV calibre?
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ADH is aka'd vasopressin -> vasoconstriction
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What is histamine's effect on BV calibre?
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Vasodilation and increased vascular permeability
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What happens to vascular calibre if we give an alpha blocker?
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alpha is engaged by NA from symp nerves -> constriction
--> if we block this with alpha blockers, get vasodilation |
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If you give an alpha blocker, do we completely relax the vascular smooth muscle?
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No. There is basal vascular tone -> if we add a smooth muscle relaxant, will get even more relaxation
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Are vascular smooth muscles tonically innervated by symp NS?
What happens if we turn off this innervation? |
Yes. Tonic innervation -> vasoconstriction
If we turn it off, get vasodilation BUT the vessel still has some degree of constriction at this point even with the symp NS turned off |
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Do vascular smooth muscle cells have some spontaneous activity?
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yes
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Why are BVs not maximally dilated when we block symp innervation of them?
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They need to still be somewhat constricted so we can get dilation when the local factors are requiring this
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What is basal vascular tone?
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The constriction of BVs that's due to vascular smooth muscle cell's spontaneous activity
(ie the constriction we still get when we stop symp innervation of the vessels) |
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What local metabolites cause vasodilation?
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- low o2
- high CO2 - lactic acid - adenosine |
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What triggers the release of NO from endothelial cells?
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Shear stress - ie if there's rapid flow past the cells, we get NO released -> vasodilation which will allow for this increased flow
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What is the main mechanism for matching local blood flow to local tissue needs?
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Intrinsic regulation ie presence / absence of local metabolites etc
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How does noradrenaline from the symp nerve cause contraction of vascular smooth muscle cell?
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2 pathways:
1. binds to alphaR -> G-protein opens Na+ ch -> cell is depol'ed -> voltage gated Ca2+ ch opens --> contraction 2. the G protein is also coupled to phospholipase C -> breaks down lipids into IP3 -> IP3 binds to Ca2+ chs on external and SR mems --> increased Ca2+ entry This second pway = pharmaco-mechanical coupling (doesn't require depolarisation) |
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Is vascular smooth muscle striated?
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No ie we don't have sarcomeres
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How do we get contraction of smooth muscle cells?
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Myosin light chain is phosphorylated -> myosin can now combine with actin --> CONTRACTION
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How do we get phosphorylation of the myosin light chain in smooth muscle?
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Ca2+ binds to calmodulin -> the complex activates the myosin light chain kinase -> adds phosphate to the myosin light chain
But the myosin light chain kinase needs to be unphosphorylated in order to be active - the kinase involved here is cGMP dependent |
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What happens if we activate cGMP in vascular smooth muscle (eg with NO)?
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cGMP -> protein kinase is activated --> it adds a phosphate group to the enzyme 'myosin light chain kinase' -> it's now inactive
-> this kinase now can't phosphorylate and hence activate the myosin light chain -> we don't get contraction |
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What is viagra's effect on cGMP levels?
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Prevents the breakdown of cGMP -> increased cGMP -> the myosin light chain kinase will get phosphorylated --> it's inactive -> the myosin light chain won't be activated -> arterioles feeding the corpus cavernosa are relaxed -> up blood flow
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