Case 6

Question 1

what’s the common basic structure of the vessels in the circulatory system?

Answer 1

• tunica intima: an inner layer comprising of a single layer of flattened endothelial cells, supported by a basement membrane and delicate collagenous tissue
• tunica media: muscular layer
• tunica externa/adventitia: supporting tissue layer

Question 2

how do the thick walls of large vessels obtain oxygen and nutrients?

Answer 2

• they cannot be sustained by diffusion of oxygen and nutrients from their lumina
• they are supplied by small arteries (vasa vasorum), which run in the tunica adventitia and sends arterioles and capillaries into the tunica media

Question 3

what are the three types of arteries?

Answer 3

1. Elastic arteries:
    - These comprise the major distribution vessels, e.g. aorta, the brachiocephalic trunk, common carotid and subclavian arteries and most of the large pulmonary arterial vessels.
2. Muscular arteries:
    - These are the main distributing branches of the arterial tree, e.g. radial, femoral, coronary and cerebral arteries.
3. Arterioles:
    - These are the terminal branches of the arterial tree which supply the capillary beds.

Question 4

what happens to the amount of elastic tissue and smooth muscle as the vessels become smaller?

Answer 4

the amount of elastic tissue decreases and the smooth muscle component assumes relatively greater prominence

Question 5

what are pericytes?

Answer 5

cells that occasionally embrace the capillary endothelial cells and may have a contractile function

Question 6

what are postcapillary venules like?

Answer 6

• Postcapillary venules have a similar structure to large capillaries with an endothelium and pericytes but no smooth muscle layer.
• Postcapillary venules drain into collecting venules which are structurally similar but larger, with more surrounding pericytes.

Question 7

what do collecting venules drain into?

Answer 7

Collecting venules drain into vessels of increasing diameter which eventually acquire a wall of smooth muscle cells two or three layers thick; at this stage the vessels are called muscular venules.

Question 8

what do large muscular veins consist of?

Answer 8

- A very narrow tunica intima.
- Tunica media is more substantial, consisting of several layers of smooth muscle separated by layers of collagenous connective tissue and scanty elastic fibres.
- Tunica adventitia is broad and is composed of collagen and contains numerous vasa vasorum (blood vessels that supply the artery itself). Elastic fibres are particularly prominent at the junction between media and adventitia, but there are no distinct elastic laminae as there are in arteries.

Question 9

what is local blood flow control divided into?

Answer 9

1. Acute control:
   - Achieved by rapid changes in local vasodilation or vasoconstriction of the arterioles, metarterioles, and precapillary sphincters.
   - Occurs within seconds to minutes to provide very rapid maintenance of appropriate local tissue blood flow.
2. Long-term control:
   - Slow, controlled changes in flow over a period of days.
   - These long-term changes provide a better control of the flow in proportion to the needs of the tissues.
   - These changes come about as a result of an increase or decrease in the physical sizes and numbers of actual blood vessels supplying the tissues.

Question 10

what is the vasodilator theory for the regulation of local blood flow?

Answer 10

• The greater the rate of metabolism, the greater the rate of formation of vasodilator substances in the tissue cells.
• The vasodilator substances diffuse through the tissues to the precapillary sphincters, metarterioles, and arterioles to cause dilation.
 - Adenosine is a particular vasodilator substance and is used in coronary circulation. Another is nitric oxide.
• Vasodilator substances increase in the tissues when blood flow is reduced and cell metabolism continues at the same rate.
• As the concentration of vasodilator metabolites increases, this causes vasodilation of the arterioles, increasing the tissue blood flow and returning the tissue concentration of the metabolites toward normal.
• Vasodilator substances may be released from the tissue in response to oxygen deficiency.

Question 11

what’s the oxygen lack theory for the regulation of local blood flow? and how relates to metarteriole and precapillary sphincters?

Answer 11

• Oxygen and other nutrients as well are required to cause vascular muscle contraction.
• If there is oxygen deficiency, blood vessels simply relax and therefore naturally dilate.
 - Increased utilization of oxygen in the tissues as a result of increased metabolism decreases the availability of oxygen to the smooth muscle fibres in the local blood vessels, and this, too, causes local vasodilation.

• The precapillary sphincters and metarterioles open and close cyclically several times per minute, with the duration of the open phases being proportional to the metabolic needs of the tissues for oxygen.
• The cyclical opening and closing is called vasomotion.
• Because smooth muscle (sphincters) requires oxygen to remain contracted, the strength of contraction of the sphincters would increase with an increase in oxygen concentration.
• Consequently, when the oxygen concentration in the tissue rises above a certain level, the precapillary and metarteriole sphincters close until the tissue cells consume the excess oxygen.
• But when the excess oxygen is gone and the oxygen concentration falls low enough, the sphincters open once more to begin the cycle again.

Question 12

• what state are precapillary sphincters normally in? what does the number open show?

Answer 12

- The precapillary sphincters are normally either completely open or completely closed.
- The number of precapillary sphincters that are open at any given time is roughly proportional to the requirements of the tissue for nutrition.

Question 13

what’s reactive hyperaemia?

Answer 13

• When the blood supply to a tissue is blocked for a certain period of time and is then unblocked, blood flow through the tissue increases immediately; this increased blood flow will last in duration around the same amount as the block.
• This phenomenon is called reactive hyperaemia.
• The extra blood flow during the reactive hyperaemia phase lasts long enough to repay the tissue oxygen deficit that has accumulated during the occlusion.

Question 14

what is acute ‘autoregulation’ of blood flow

Answer 14

• In any tissue of the body, a rapid increase in arterial pressure causes an immediate rise in blood flow.
• But, within a minute, the blood flow in most tissues returns to the normal level, even though the arterial pressure is kept elevated.
• This return of flow toward normal is called acute “autoregulation” of blood flow.

• After autoregulation has occurred, the local blood flow in most body tissues will be related to arterial pressure approximately in accordance with the solid “acute” curve.

Question 15

what’s the metabolic theory to explain the acute autoregulation mechanism?

Answer 15

• This theory states that when the arterial pressure becomes too great, the excess flow provides too much oxygen and too many other nutrients to the tissues and “washes out” the vasodilators released by the tissues.
• These nutrients (especially oxygen) and decreased tissue levels of vasodilators then cause the blood vessels to constrict and the flow to return nearly to normal despite the increased pressure.

Question 16

what’s the myogenic theory to explain the acute autoregulation mechanism?

Answer 16

• Sudden stretch of small blood vessels causes the smooth muscle of the vessel wall to contract.
• It has been proposed that when high arterial pressure stretches the vessel this causes reactive vascular constriction that reduces blood flow nearly back to normal.
• At low pressures, the degree of stretch of the vessel is less, so that the smooth muscle relaxes, reducing vascular resistance and helping to return flow toward normal.
• The myogenic mechanism prevents excessive stretch of blood vessel when blood pressure is increased.

Question 17

what are two mechanisms released by the endothelium that can affect the degree of relaxation or contraction of the arterial wall?

Answer 17

• nitric oxide

- endothelin

Question 18

what is nitric oxide (NO) released in response to?

Answer 18

to a parasympathetic nervous system stimulation

• NO synthesis and release from endothelial cells are also stimulated by some vasoconstrictors, such as angiotensin II, which bind to specific receptors on endothelial cells.
 The increased NO release protects against excessive vasoconstriction

Question 19

what are the direct and indirect pathways of nitric oxide?

Answer 19

o Direct pathway: the PNS uses NO as a neurotransmitter and has a direct effect on the smooth muscle cells. The drug GTN, once converted into NO, acts directly on the smooth muscle cells.
o Indirect pathway: the PNS uses acetyl choline as a neurotransmitter and stimulates the endothelial cells to produce NO, which then act on the smooth muscle cells.

Question 20

how is NO synthesised?

Answer 20

Nitric oxide synthase (NOS) enzymes in endothelial cells synthesize NO from arginine and oxygen and by reduction of inorganic nitrate.

Question 21

what does NO do? and mechanism?

Answer 21

- Activates guanylate cyclase (G-cyclase).
- This increases formation of cGMP, which activates protein kinase G.
- This leads to the dephosphorylation of myosin light chains and sequestration of intracellular Ca2+, with consequent relaxation.

Question 22

explain how the local metabolic mechanisms for controlling tissue flow have an effect across the body

Answer 22

- When blood flow through a microvascular portion of the circulation increases, this secondarily stimulates the release of NO from larger vessels due to increased flow and shear stress in these vessels.
- The released NO increases the diameters of the larger upstream blood vessels whenever microvascular blood flow increases downstream.
- Without such a response, the effectiveness of local blood flow control would be decreased because a significant part of the resistance to blood flow is in the upstream small arteries.

Question 23

what happens when endothelial cells are damaged by chronic hypertension or atherosclerosis?

Answer 23

impaired NO synthesis may contribute to excessive vasoconstriction and worsening of the hypertension and endothelial damage

Question 24

endothelin

• where’s it present
• when does it increase
• what does it cause

Answer 24

• Endothelin is present in the endothelial cells of all blood vessels.
• It greatly increases when the vessels are injured.
• After severe blood vessel damage, release of local endothelin and subsequent vasoconstriction helps to prevent extensive bleeding from arteries.

Question 25

what happens if a tissue becomes chronically overactive?

Answer 25

the arterioles and capillary vessels usually increase both in number and size within a few weeks to match the needs of the tissue - this process is called angiogenesis

- It is faster and more complete in the young.
- Vascularity increases in those living in low oxygen environments demonstrating oxygen’s importance in long-term oxygen control.

Question 26

what stimulates vascular endothelial growth factor (VEGF) and other angiogenic factors that promote vessel growth?

Answer 26

relative lack of oxygen in tissues

Question 27

how do these factors cause new vessels to sprout from current vessels?

Answer 27

1. The first step is dissolution of the basement membrane of the endothelial cells at the point of sprouting.
2. Followed by rapid reproduction of new endothelial cells that stream outward through the vessel wall in extended cords directed toward the source of the angiogenic factor.
3. The cells in each cord continue to divide and rapidly fold over into a tube.
4. Next, the tube connects with another tube budding from another current vessel and forms a capillary loop through which blood begins to flow.
5. If the flow is great enough, smooth muscle cells eventually invade the wall, forming arterioles or venules or even larger vessels.

Question 28

what is collateral circulation? what are the stages?

Answer 28

• When an artery or a vein is blocked, a new vascular channel usually develops around the blockage and allows at least partial resupply of blood to the affected tissue.

1. The first stage in this process is dilation of small vascular loops that already connect the vessel above the blockage to the vessel below.
    - This is insufficient to provide the nutrients to the tissues.
2. Further dilation occurs within hours/days and provides sufficient blood flow.
3. The collateral vessels continue to grow for many months thereafter, almost always forming multiple small collateral channels rather than one single large vessel.
    - The new channels rarely become large enough to supply the blood flow needed during strenuous tissue activity.

Question 29

what is the equation for blood pressure?

Answer 29

blood pressure = cardiac output (CO) x total peripheral resistance (TRP)

Question 30

what is stroke volume affected by?

Answer 30

1. Preload: the tension in the cardiac myocytes before they contract. Frank Starlings Law of the Heart (dependent on venous return).
2. Contractility: the contraction force of the myocardium for a given preload.
3. Afterload: the blood pressure in the aorta and pulmonary trunk.

Question 31

what is heart rate increased and decreased by?

Answer 31

increased by:
- epinephrine and norepinephrine; increase in temperature; thyroid hormone

decreased by:
- acetylcholine; decreases in temperature; intense visceral pain

Question 32

what can total peripheral resistance be affected by?

Answer 32

1. Viscosity of the blood which remains relatively stable.
2. Vessel length which remains unchanged.
3. Vessel radius which changes.

Question 33

what is sympathetic tone? (or vasomotor tone)

Answer 33

normally, blood vessels are maintained in state of partial vasoconstriction

Question 34

what determines the vessel radius? what controlled by?

Answer 34

• Determined by the sympathetic nervous system.
• Normally, blood vessels are maintained in state of partial vasoconstriction. This is known as the sympathetic tone (or vasomotor tone).
• Increased SNS activity: vasoconstriction.
• Decreased SNS activity: vasodilation.
• This is all controlled by the vasomotor centre in medulla oblongata.

Question 35

neural mechanism

• which receptors
• where found
• which afferent nerves to where

Answer 35

• Maintains the blood pressure around a set point.
• Baroreceptors (mechano/stretch receptors):
 - Found in the carotid and aortic sinuses.
 - Carotid sinus sends impulses to the brain via the glossopharyngeal nerve.
 - Aortic sinus sends impulses to the brain via the vagus nerve.
• These afferent nerve fibres carry information from the baroreceptors to the nucleus solitarius in the brain stem.
• Nucleus solitarius (NTS): this is a series of nuclei forming a vertical column of grey matter embedded in the medulla oblongata. Through the centre of the NTS runs the solitary tract, a white bundle of nerve fibres, including fibres from the glossopharyngeal and vagus nerves that synapse on neurons of the NTS
• Nucleus solitarius modulates the activity of the cardiovascular centres.

Question 36

what are the cardiovascular centres?

Answer 36

Vasomotor centre and Cardiac Accelerator centres:
o Groups of sympathetic neurones in the medulla.
o Vasomotor means “causing or relating to the constriction or dilatation of blood vessels.”

Cardiac Inhibitory centres:
o Dorsal motor nucleus of the Vagus nerve and the Nucleus Ambiguus.

Question 37

describe how the vasomotor centre works

Answer 37

• This centre transmits:
1. Parasympathetic impulses through the vagus nerves to the heart.
2. Sympathetic impulses through the spinal cord and peripheral sympathetic nerves to virtually all arteries, arterioles and veins of the body.
• A vasoconstrictor area excites preganglionic vasoconstrictor neurons of the sympathetic nervous system.
• The fibres from the neurons in a vasodilator area project upward to the vasoconstrictor area; they inhibit the vasoconstrictor activity of this area, thus causing vasodilation.
• The neurons of the sensory area receive sensory nerve signals from the circulatory system (through receptors) mainly through the vagus and glossopharyngeal nerves, and output signals from this sensory area then help to control activities of both the vasoconstrictor and vasodilator areas of the vasomotor centre.

• The lateral portions of the vasomotor centre transmit excitatory impulses to increase heart rate and contractility.
• The medial portion of the vasomotor centre sends signals to the vagus nerves to decrease heart rate and heart contractility.
• The substance secreted at the vasoconstrictor nerve endings is almost entirely norepinephrine.
• The substance secreted at the vagal nerve endings is acetyl choline.

Question 38

describe how baroreceptors work

Answer 38

- These are found in the carotid and aortic sinuses.
- These transmit continual signals to cardiac and vasomotor centres:
o An increase in blood pressure:
 Increases the firing rate to cardiac and vasomotor centres:
1. Stimulates cardioinhibitory centre which increases the activity of the parasympathetic nervous system to the SA node, thus decreasing the heart rate.
2. Inhibits cardioaccelerator and vasomotor centres which decreases the activity of the sympathetic nervous system, thus decreasing the heart rate and causing vasodilation.
o A decrease in blood pressure:
 Decreases the firing rate to cardiac and vasomotor centres:
1. Stimulates cardioaccelerator and vasomotor centres which increases the activity of the sympathetic nervous system to the SA node, thus increasing the heart rate, force of contraction and causing vasoconstriction.
2. Inhibits cardioinhibitory centre which decreases the activity of the parasympathetic nervous system to the SA node, thus increasing the heart rate.

Question 39

what’s the humoral control of blood pressure (which hormones)?

Answer 39

- Catecholamines: adrenaline and noradrenaline
- Renin Angiotensin Aldosterone System (RAAS)
- Atrial Natriuretic Peptide (ANP)
- Antidiuretic Hormone (ADH)

Question 40

catecholamines

• where released
• what stimulates release
• what bind to - all different types of receptors

Answer 40

- These are released by the adrenal medulla: 80% adrenaline and 20% noradrenaline.
-	The medulla is stimulated by stress (not necessarily bad stress) 
Stress: 
-	Exercise 
-	Blood loss 
-	Emotion 
-	Excitement 
-	Pain 

- These bind to alpha and beta receptors.

Alpha receptors:
o α1 receptors on vascular smooth muscle cause vasoconstriction.
o α2 receptors on presynaptic membrane cause negative feedback.

Beta receptors:
o β1 receptors on SA node and cardiac muscle cause increase in heart rate and contraction force.
o β2 receptors on vascular smooth muscle in coronary arteries and skeletal muscles cause vasodilation.
o β2 receptors on airway smooth muscle cause bronchodilation.
o β3 receptors on adipocytes cause lipolysis.

Question 41

renin angiotensin aldosterone system (RAAS)

• what’s renin
• what does it do
• how stored and formed
• what stimulates
• what inhibits it

Answer 41

- Renin is a protein enzyme released by the kidneys when the arterial pressure falls too low.
- In turn, it raises the arterial pressure in several ways, thus helping to correct the fall in pressure.
- Renin is synthesized and stored in an inactive form called prorenin in the juxtaglomerular cells (JG cells) of the kidneys
- When the arterial pressure falls, intrinsic reactions in the kidneys themselves cause many of the prorenin molecules in the JG cells to split and release renin.

- Reduced Na+ can stimulate renin directly.
- Angiotensin II and ANP inhibit renin.

Question 42

describe the renin angiotensin aldosterone system

Answer 42

1. A decrease in renal perfusion, a decrease in sodium delivery to distal tubule of the kidney or sympathetic stimulation cause the release of renin.
2. Renin acts enzymatically on angiotensinogen to release a 10-amino acid peptide, angiotensin I.
3. The enzyme, Angiotensin Converting Enzyme (ACE), removes two amino-acids from Angiotensin I to form the 8-amino acid peptide angiotensin II.
4. This conversion occurs to a great extent in the lungs while the blood flows through the small vessels of the lungs. ACE is present in the endothelial cells of the vessels in the lungs.
5. Other tissues such as the kidneys and blood vessels also contain converting enzyme and therefore form angiotensin II locally.
6. Angiotensin II has many effects:
    - Powerful vasoconstriction of arterioles causing an increase in the blood pressure.
    - Aldosterone stimulation:
    - Aminopeptidase A cleaves angiotensin II forming Angiotensin III which stimulates aldosterones and is involved in increasing thirst.
   o Aldosterone increases the reabsorption of Na+ ions and water in the distal tubules and collecting ducts.
   o It causes an increase in blood pressure.

Question 43

describe how ADH works

Answer 43

- Angiotensin II makes the patient thirsty.
- This increases the secretion of ADH to increase water reabsorption.
- ADH increases the blood volume and so increases the blood pressure.

Question 44

atrial natriuretic peptide

• what stimulates secretion
• what are its effects

Answer 44

This peptide is secreted if there is excess stretching of the cardiac myocytes, as a result of increased blood volume, or through the effects of Angiotensin II on the heart.

ANP has many effects:
o Decreases the release of renin and aldosterone.
o ANP is a powerful vasodilator.
o Increases the GFR (glomerular filtration rate), causing increased natruiresis and diuresis.
o These effects decrease the blood volume, cardiac output and blood pressure.

Question 45

what is hypertension?

Answer 45

an increase in peripheral vascular resistance when the cardiac output is normal

this means that there is vasoconstriction of small arteries throughout the body, resulting in an increase in the cardiac output to compensate for the reduced blood flow to the peripheries, thus increasing the blood pressure

clinically defined as blood pressure that is > 140/90 mmHg

Question 46

what’s primary hypertension? how common?

Answer 46

98% of hypertension patients have Primary Hypertension:

- Primary hypertension isn’t associated with a particular cause.
 - Genetic (family history) and environmental factors (obesity, high alcohol intake, high salt intake).
 - Autonomic neural dysfunction:
o Increased autonomic stimulation causes increased secretion of catecholamines, resulting in vasoconstriction and subsequent increase in the blood pressure.

Question 47

what’s secondary hypertension? how common?

Answer 47

2% of hypertension patients have Secondary Hypertension:
- Secondary hypertension is associated with many causes:
o Tumour of adrenal glands (produce excess catecholamines).
o Kidney disease (increased renin – increased angiotensin II – vasoconstriction).
o Genetic disorders
o Drugs (OCP) liquorice (salt retention – increases blood pressure)

Question 48

what’s the pathophysiology of hypertension? how does it come about? - old and young patients

• how does hypertension affect large arteries
• what does this result in
• what do these changes eventually lead to

Answer 48

• In young patients there may be an early increase in the cardiac output in association with increased circulating catecholamines.
• In chronic hypertension, the cardiac output is normal and it is an increased peripheral resistance that maintains the elevated blood pressure:
  o There is an increase in arteriole wall thickness with a reduction in the vessel lumen diameter.
  o Rarefaction (decreased density) of these vessels.
  o Increased smooth muscle cell matrix synthesis in response to chronic hemodynamic stress.
• These mechanisms would result in an increased overall peripheral vascular resistance.

Hypertension affects the large arteries in the following way:
o Thickening of the media
o Increase in collagen
o Secondary deposition of calcium

These changes result in:
o A loss of arterial compliance (stretchability).
o Development of atheromas in the large arteries.
o Endothelial dysfunction: alternations in agents such as nitric oxide and endothelin secretion.
o Left ventricular hypertrophy (LVH): results from increased peripheral vascular resistance and increased left ventricular load (increased pressure in aorta against which LV has to pump blood out of the heart).
 - LVH is a significant prognostic indicator of future cardiovascular events.

Changes in the renal vasculature eventually lead to:
o A reduced renal perfusion
o Reduced glomerular filtration rate
o A reduction in sodium and water excretion
- The decreased renal perfusion may lead to activation of the renin–angiotensin system with increased secretion of aldosterone and further sodium and water retention.

Question 49

what are investigations for hypertension?

Answer 49

- Plasma glucose; serum lipid profile (cholesterol, HDL, LDL, triglycerides); serum creatinine; serum potassium; ECG.
- The serum potassium is decreased in patients with hypercholesterolaemia.

Question 50

what’s the effect of nicotine and how does it have this effect?

Answer 50

- Nicotine binds to the nicotinic cholinergic receptors on the preganglion of the SNS in the brain; it can do this because it shares chemical similarities with acetylcholine.
- Activation of the receptor causes the release of catecholamines, which is responsible for the acute effects of smoking (fight or flight stress defences):
o Increase in heart rate
o Increase in blood pressure
o Elevation in cardiac contractility
o Elevation in cardiac output

Question 51

how does carbon monoxide cause atherosclerosis?

Answer 51

The inside of each healthy blood vessel is coated with a thin layer of cells that ensure smooth blood flow.
 - Carbon monoxide from smoking or second-hand smoke damages this important layer of cells, causing atherosclerosis.

Question 52

amlodipine

• what is it
• what used to treat
• mechanism of action
• interactions
• side effects

Answer 52

• This is a long-acting calcium-channel antagonist.
• It is used to treat hypertension and prevent angina pectoris.
• It is administered by mouth.
• Mechanism of Action:
 - Antagonist for the L-type calcium channels.
 - Amlodipine decreases arterial smooth muscle contractility and vasoconstriction by inhibiting the influx of calcium ions through L-type calcium channels.
 - The vasodilation and decreased cardiac output result in an overall decrease in blood pressure.
• Interactions:
 - Grapefruit juice increases the serum amlodipine levels and may cause toxicity.
• Side effects:
 - Headache; dizziness; fatigue; nausea; fluid retention; hypotension.

Question 53

Chlorthalidone

• what is it
• what used to treat
• mechanism of action
• side effects

Answer 53

• This is a thiazide-like diuretic.
• It is used to treat fluid retention, hypertension and heart failure.
• It is administered by mouth.
• Mechanism of Action:
 - Thiazide diuretics bind to the chlorine binding site on the tubular epithelium, inhibiting the Na/Cl symport, thereby inhibiting Na reabsorption.
 - Since water will osmotically follow Na, the reabsorption of water is inhibited (diuretic action).
 - Inhibits sodium ion transport across the renal tubular epithelium in the cortical (in cortex) diluting segment of the ascending loop of Henle.
 - Because loop and thiazide diuretics increase sodium delivery to the distal segment of the distal tubule, this increases potassium loss (potentially causing hypokalemia) because the increase in distal tubular sodium concentration stimulates the aldosterone-sensitive sodium pump to increase sodium reabsorption in exchange for potassium and hydrogen ion, which are lost to the urine.
• Side effects:
 - Postural hypotension; dizziness; hypokalaemia; hyponatraemia

Question 54

Candesartan

• what is it
• what used to treat
• mechanism of action
• side effects

Answer 54

• This is an angiotensin II receptor antagonist.
• It is a prodrug.
• It is used to treat hypertension.
• Mechanism of Action:
 - It selectively blocks the binding of angiotensin II to its receptor.
 - This occurs in many tissues, including vascular smooth muscle and the adrenal glands.
 - This inhibits angiotensin II receptor-mediated vasoconstrictive and aldosterone-secreting effects of angiotensin II.
 - This results in an overall decrease in blood pressure.
 - Inhibition of aldosterone may increase sodium and water excretion while decreasing potassium excretion.
• Side effects: Hypotension; hyponatraemia

Question 55

what are the effects of smoking on the cardiovascular system?

Answer 55

• Nitric oxide, a free radical, is primarily responsible for the vasodilatory function of the endothelium
• Multiple studies have found that cigarette smoking was associated with decreased nitric oxide availability
• NO also helps regulate inflammation, leukocyte adhesion, platelet activation, and thrombosis
• Therefore, an alteration in NO biosynthesis could have both primary and secondary effects on the initiation and progression of atherosclerosis and on thrombotic events

Atherosclerosis:
- Cigarette smoking increases blood cholesterol levels, causing a build-up of arterial plaque that narrows the blood vessels over time

Blood clots:

• Less room for blood to flow within the blood vessels that lead to the heart and brain leaves tobacco users more vulnerable to heart attacks and strokes
• Smoking makes blood platelets sticky and prone to clotting

Low blood oxygen:

• Another possible contingency of tobacco use is pulmonary hypertension, or high blood pressure between the lungs and heart
• Reduced capacity of cardiopulmonary blood vessels to exchange oxygen and carbon dioxide,
• Oxygen levels are already compromised in smokers, who ingest carbon monoxide
• Pulmonary hypertension further reduces oxygen levels
• A heart damaged by cigarette smoking may not be able to pump more blood to get a greater volume of oxygen to the cells – resulting in congestive heart failure

Question 56

what are the pro-inflammatory effects of smoking on the cardiovascular system?

Answer 56

• The inflammatory response is an essential component in the initiation and evolution of atherosclerosis
• Several studies have indicated that cigarette smoking causes about a 20% to 25% increase in the peripheral blood leukocyte count
• Smoking is associated with an increased level of multiple inflammatory markers including C-reactive protein, interleukin-6, and tumour necrosis factor
• Local recruitment of leukocytes on the surface of endothelial cells is an early event in atherosclerosis
• Elevations of various proinflammatory cytokines increase leukocyte-endothelial cell interaction leading to leukocyte recruitment

Question 57

what is oncotic pressure? what is hydrostatic pressure?

Answer 57

• A form of pressure in the circulatory system which encourages water to cross the barrier of the capillaries and enter the circulatory system
• In patients with low oncotic pressure, fluid will tend to accumulate in the tissues, resulting oedema
• Hydrostatic pressure is the force which pushes fluids over the membrane and out of the circulatory system, while oncotic pressure is the force which brings fluids back into the circulatory system
• When these two forces are in balance, there is no net loss or gain of fluid from the circulatory system

Question 58

what’s osmotic pressure?

Answer 58

• A volumetric force that resists the natural process of osmosis
• The natural process of osmosis tends to equalise the concentrations of solute materials in a solution by passing the solution through such membranes, and osmotic pressure is the quantity of pressure that a living cell exerts to resist this force
• Such pressure protects inner components of the cell from dilution and harmful solutions that might cross the membrane and disrupt normal cell activity or mitosis

Question 59

how does blood pressure change throughout the day?

Answer 59

• Blood pressure is normally lower at night while you’re sleeping
• Your blood pressure starts to rise a few hours before you wake up
• Your blood pressure continues to rise during the day, usually peaking in the middle of the afternoon
• Then in the late afternoon and evening, your blood pressure begins dropping again

Question 60

what are resistance vessels?

Answer 60

• The blood vessels, including small arteries, arterioles, and metarterioles that form the major part of the total peripheral resistance to blood flow
• Blood vessels that convert high pressure, pulsatile arterial blood flow to low-pressure, non-pulsatile flow at the precapillary sphincter, to allow normal capillary function

WHAT IS A ‘RESISTANCE ARTERY’?
Constriction and dilation on the outside contributes to change in blood pressure centrally

Question 61

which organs are especially sensitive to changes in BP?

Answer 61

• kidneys
• brain
• heart

Question 62

what happens when you have a haemorrhage and blood volume isn’t replaced after a little while?

Answer 62

• Venous return continues to fall -> decrease EDV
• Heart rate increases -> decreasing filling time -> decrease EDV
• Decrease EDV -> decrease force of contraction (Starling’s Law of the Heart – less stretch of cardiomyocytes)
• Decrease stroke volume, decrease CO, decrease blood pressure

Question 63

how can calcium induce vasodilation?

Answer 63

• Influx of extracellular calcium constricts the artery when pressure is present
• However, calcium is also released by the vascular smooth muscle events as small ‘release events’ – calcium sparks (released from sarcoplasmic reticulum)
• These are vasodilatory signals – i.e. a dual role for calcium – calcium both constricts and dilates arteries!

Calcium spark -> activation of calcium sensitive potassium channels (BK) -> efflux of potassium from cell -> membrane hyperpolarisation -> inactivation of voltage dependent calcium channels -> reduction in free cytoplasmic calcium -> relaxation

Question 64

what happens with obesity?

Answer 64

you decrease the vasodilation from calcium sparks

Question 65

what happens in the anticipation of exercise?

Answer 65

Just the thought of exercise is enough to trigger some preparation:
Cerebral cortex -> hypothalamus -> CRF (corticotropin releasing factor) released -> anterior pituitary releases ACTH (adrenocorticotrophic hormone) -> adrenal gland produces adrenaline -> heart increases rate, increase ventilation rate, increase glucose available from liver through gluconeogenesis & glycogenolysis

Question 66

why is there not Va/Q mismatch during exercise?

Answer 66

• increase VA (alveolar ventilation) during exercise as greater demand for oxygen
• relies on lung’s ability to increase surface area for diffusion
  Why does this not lead to Va/Q mismatch?
• Because blood flow increases through pulmonary capillaries -> physiological dead space drops from 33% to 15%

Question 67

what drives increase in ventilation during exercise?

Answer 67

increase in CO2

• Oxygen uptake to VA is linear up to 60% of maximum oxygen consumption, but then you go above 60% and it’s exponential – no longer possible to supply sufficient oxygen to the muscles, and so anaerobic respiration takes place – lactic acid produced, which displaces carbon dioxide, so carbon dioxide is released into the blood
• Whereas CO2 production is linear to VA is, so it’s the increase in CO2 that drives the increase in ventilation

Question 68

what does diastolic pressure measure?

Answer 68

it measures the pressure in your blood vessels between heartbeats

Question 69

what’s an indication of high level of ischaemia and damage to heart in terms of maximum predicted heart rate?

Answer 69

not reaching 85% of their maximum predicted heart rate

Question 70

why is there an increase in blood volume during exercise?

Answer 70

REDISTRIBUTION OF BLOOD
Increase blood volume due to:
- Vasoconstriction of veins -> increase VR
- Decrease renal blood flow -> decrease glomerular filtration
- Skeletal muscle pump (muscles of leg contract) -> movement of blood from peripheral veins to heart
- Respiratory pump (increase inspiration, decrease thoracic pressure, draws blood into cavity -> increase VR
- Vasoconstriction of spleen – allows more blood to enter systemic circulation

Question 71

what is frank-starling’s law, explain it and what does this law account for?

Answer 71

The Frank–Starling law of the heart states that the stroke volume of the heart increases in response to an increase in the volume of blood filling the heart (the end diastolic volume) when all other factors remain constant.

• Increase venous return -> increase load on each muscle fibre -> increase stretch -> increase contractility
• Accounts for the increase SV despite reduced filling time

(stretch creates optimal overlap of actin and myosin = higher strength of contraction – to do with the degree of overlap and number of cross-bridges forming)

Question 72

what happens to blood flow during exercise? where does it go?

Answer 72

At rest - % cardiac output (5 L/min) 
-	27% skeletal muscle 
-	73% kidneys, GIT, heart, brain 
During dynamic - % cardiac output (25 L/min)
-	85% skeletal muscle 
-	Kidneys, GIT, heart, brain  

Important = blood flow to brain decreases

Question 73

what increases O2 extraction by muscles?

Answer 73

• At rest, skeletal muscle extracts about 25% delivered O2
• During exercise, blood flow redistributed from metabolically less active cells to exercising muscle – so BP in muscle capillaries is increased -> fluid loss from exercising muscle into interstitial space (at same time cells producing metabolites which increase the oncotic pressure = draw fluid out of blood -> haemoconcentration (as water from blood drawn out) = haemoglobin more concentration -> therefore greater oxygen gradient from blood to muscle -> increase O2 extraction

Question 74

what is VO2 max? why’s it useful? what happens once reached it? how can it be changed?

Answer 74

Good indicator of cardiovascular endurance

• Max capacity to transport/utilise O2 during incremental exercise (units: ml/min/kg)
• 30-40 in women and 40-50 in men (under 40)
• i.e. VO2 increases rapidly after an increase in exercise workload -> VO2 max reached when VO2 remains at stead state despite increased workload
• once reached VO2max there is no more capacity for aerobic respiration and therefore switch completely to anaerobic respiration and fatigue occurs very quickly
• in sedentary people, VO2max can be increased by up to about 90%
• requires high intensity & vol. of training long-term
• little change in athletes

Question 75

what are the effects of training on the heart? and what does this mean for when you train?

Answer 75

• adaptions in coronary microvessels:
• increase arteriolar density (may be proportional to degree of hypertrophy)/diameter -> increase blood flow
• increase recruitment of capillaries
• hypertrophy of myocardial muscle -> increase force of contraction

So, if you are well trained aerobically, your heart rate and blood pressure won’t have to increase as much when you do exercise

Question 76

effect of training on blood vessels?

Answer 76

• > acts on pressure-sensitive ion channels -> upregulation of endothelial NOS (nitric oxide synthase) -> nitric oxide causes local relaxation of vascular smooth muscle = vasodilation
• > acts on pressure-sensitive ion channels -> release of GFs, metalloproteinases, etc. -> angiogenesis (growth of new blood vessels)

Question 77

what counts as hypertension at home?

Answer 77

130/85

Question 78

give a summary of antihypertensive drug treatment - what are the different combinations

Answer 78

A = ACE inhibitor or low-cost angiotensin II receptor blocker (ARB) 
C = Calcium-channel blocker (CCB)
D = Thiazide-like diuretic 

Consider monotherapy in low risk stage 1 hypertension
Dual combination 1 = A + C or D = 1 pill (what most people are on) (in some patients C + D)
Triple combination 2 = A + C + D = 1 pill
Triple combination + additional 3 = resistant hypertension – add spironolactone or further diuretic – consider referral to specialist centre for further investigation = 2 pill

Consider beta-blockers when there is a specific indication, e.g. heart failure, angina, post-MI
Do not combine ACE with ARB

Question 79

what are loop diuretics? how strong is their action?

Answer 79

Ascending loop of Henle is the one place where water doesn’t move where ions move, as its impermeable to water but salts are reabsorbed there

In ascending limb:
On side of cell that points into the lumen there’s a sodium-potassium 2-chloride transporter
- Sodium, potassium and 2 x chloride get removed from the tubule, but water doesn’t follow
Loop diuretics = diuretics that inhibit that transporter
What happens with these diuretics?
- The fluid in the ascending loop of Henle now becomes quite concentrated – the salts stay behind
- This draws water into the tubules by osmosis
- So, you get more water removed from the body
Loop diuretics are not used as antihypertensive drugs, except in certain types of situations, instead they are more used to reduce oedema
- They are very powerful become of where they act in the tubules

Question 80

what are thiazide diuretics? how strong is their action?

Answer 80

• Block the sodium-chloride co-transporter in the distal convoluted tubule
• So, blocking the reabsorption of sodium and chloride into the body – so increase salt concentration in the DCT and so more water drawn in, so more water loss
• They have a much weaker effect than the loop diuretics, which have a very strong effect as they work on the ascending limb where its impermeable to water, so water can’t move out and back into blood stream
• They are antihypertensive

Question 81

what’s an example of a loop diuretic?

Answer 81

furosemide

Question 82

how do most drugs that cause vasodilation work?

Answer 82

by lowering Ca2+ levels in the smooth muscle cells

Question 83

what mechanisms cause contraction of muscle cells?

Answer 83

• GPCR (G protein coupled receptor) -> agonist binds -> activates phospholipase C which cleaves phospholipids in the membrane into IP3 and DAG
• The IP3 binds to receptors in the sarcoplasmic reticulum – the receptor is a receptor-gated ion channel, which results in calcium leaving the SR going into the cytosol
• The DAG activates protein kinase C which causes calcium sensitisation – so maintain contraction without much energy
• The calcium then goes on to do other things
• There’s a calcium activated chloride channel in the membrane, so when calcium binds to it the channel opens and chloride ions flow out of the cell down their electrochemical gradient for chloride – result is depolarisation of the membrane which opens voltage-gated calcium channels
• Now calcium can enter the cell and add to the calcium in the cytoplasm
• The receptor operated channels then open – ion channels that when opened allow cations/sodium ions into the cell – this depolarises the membrane and stimulates the activation of the calcium channels
• So, you have several mechanisms adding to the calcium in the cell

Question 84

what causes muscle relaxation?

Answer 84

Relaxation:

• K+ channels mediate potassium efflux which hyperpolarises the cell and inhibits the calcium channels – these potassium channels can also be activated by calcium
• A mechanism to remove calcium is uptake back into the sarcoplasmic reticulum through the SERCA
• Calcium is also removed through the membrane – plasma membrane Ca2+ ATPase (PMCA)
• Another mechanism is that calcium is removed from the cell in exchange for sodium entry

Question 85

how do calcium antagonists target one of these mechanisms?

Answer 85

• The major one targeted is the VOCC – targeted by calcium antagonists – it binds to the voltage-operated calcium channels and prevents calcium entry

Question 86

what’s a general mechanism used by lots of different receptors as an antihypertensive?

Answer 86

• The other type of drug used is the receptor antagonist – general mechanism used by lots of different receptors – e.g. GPCR antagonist – prevents all the pathways from happening

Question 87

explain the renin angiotensin aldosterone system - my notes

Answer 87

• Renin made in kidneys
• Angiotensinogen made in liver
• When these two come together in plasma
• Renin cleaves angiotensinogen into a short peptide – angiotensin I (has some vasoconstrictor action but not very potent)
• If make it smaller by creating angiotensin II = very potent vasoconstrictor – made anywhere in circulation, but main place is as it passes through the lungs – a lot of angiotensin converting enzyme in the lung
• Angiotensin II has many effects – all mediated by its interaction with angiotensin 1 (AT1) receptor
• Promotes vasoconstriction (direct effect on smooth muscle (AT1 receptors on smooth muscle) & via NE release from sympathetic nerves (AT1 receptors on presynaptic nerve terminals, which release noradrenaline))
• Angiotensin II also has more long-term effects on the smooth muscle – causes vascular growth (hyperplasia, hypertrophy) – a thickening of muscle in the vessels, which can narrow the lumen, not by vasoconstriction but by having a thicker wall
• Thirdly, angiotensin II acts on the adrenal glands to stimulate the production of aldosterone (mineralocorticoid involved in regulating salt and water retention)
• Aldosterone then acts back on the kidney – acts on sodium-potassium ATPase in cells of the distal tubule and normally results in the reabsorption of sodium ions and the excretion of potassium ions – more retention of water