PBL 6 - regulation of vascular tone via calcium signalling

Question 1

what do global cytoplasmic calcium levels determine?

Answer 1

contractility

Question 2

what do localise calcium signals within the cytoplasm do?

Answer 2

activate nearby K+ channels to cause hyperpolarisation and thus vasodilation

Question 3

how do we treat patients with small vessel disease of the kidney?

Answer 3

dialysis (bypass kidney)

Question 4

how do we treat patients with small vessel disease of the eye?

Answer 4

use laser gun to photocoagualte the retina — burn away all the dysfunctional arteries

Question 5

how do we treat patients with small vessel disease of the brain (eg. vascular dementia)?

Answer 5

no treatment — institutional care

Question 6

what are 3 macro vascular complications of when small arteries don’t function properly?

Answer 6

• stroke
• heart disease
• peripheral vascualr disease

Question 7

what are 3 micro vascular complications of when small arteries don’t function properly?

Answer 7

• diabetic retinopathy
• diabetic nephropathy
• diabetic neuropathy

Question 8

describe the endothelial lining of blood vessels

Answer 8

• monolayer

- endothelial cells run parallel to flow

Question 9

describe the vascular smooth muscle of blood vessels

Answer 9

• vascular smooth muscle cells wrap around the lumen of the artery
• constrict — lumen gets smaller

Question 10

what separates the endothelial monolayer from the thick muscular wall?

Answer 10

internal elastic lamina

Question 11

equation for mean BP

Answer 11

BP = CO x TPR

Question 12

what determines whether a vascular smooth muscle cell constricts or relaxes?

Answer 12

it’s electrical membrane potential (their electrical activity)

Question 13

what is the most numerous ion channel in the plasma membrane of vascular smooth muscle cells?

Answer 13

K+ channels

Question 14

what happens when K+ channels open?

Answer 14

• K+ leaves the cell as an intracellular ion

- hyperpolarisation — cell becomes more -ve

Question 15

what happens when K+ channels close?

Answer 15

• inside of cell becomes more +ve = depolarisation

Question 16

in what layer are smooth muscle cells located?

Answer 16

tunica media

Question 17

describe a cross section of a blood vessel wall

Answer 17

• endothelium
• tunica intima
• IEM
• tunica media — smooth muscle
• EEM
• tunica externa

Question 18

how do changes in the membrane potential effect of the contractile of the artery?

Answer 18

by influencing the activity of voltage-dependent calcium channels

Question 19

what happens when the MP is lowered to result in reduced contractility of the artery?

Answer 19

• the cell becomes hyperpolarised due to K+ efflux
• voltage-dependent calcium channels become inactivated
• less Ca++ can enter the cytoplasm globally
• reduced contractility of the artery

opposite when cell is depolarised

Question 20

what is the link between K+ and vasodilation/vasoconstriction?

Answer 20

K+ channels open = K+ leaves cell = vasodilation

K+ channels close = K+ doesn’t leave cell = vasoconstriction

Question 21

what is the main channel that significantly impacts the resting tone of the small artery?

Answer 21

large conductance calcium-activated K+ channel = BKca

Question 22

describe large conductance calcium-activated K+ channels (BKca)

Answer 22

• voltage dependent

- activated by small, very high concentrations of Ca++ — calcium release events from the sarcoplasmic reticulum

Question 23

what causes contraction of arteries?

Answer 23

pressure — don’t contract and relax, just squeeze

Question 24

how does pressure affects arterial Ca++ and hence lead to constriction?

Answer 24

increase in pressure = increase in arterial Ca++

• increase in intraluminal pressure
• artery stretches
• senses Ca++ in cytoplasm
• contractile process so therefore the artery squeezes

Question 25

what happens if a drug blocks the voltage-gated Ca++ channels?

Answer 25

- no rise in arterial Ca++ | - when the artery is stretched, it doesn’t constrict

Question 26

describe the dual role of Ca++

Answer 26

1. the global level of Ca++ determines how hard the artery squeezes 2. Ca++ is released by the vascular smooth muscle endoplasmic/sarcoplasmic reticulum as small ‘release events’ = calcium sparks — activated the K+ channels to cause hyperpolarisation

Question 27

describe how intraluminal pressure leads to pressure induced constriction

Answer 27

1. intraluminal pressure 2. membrane depolarisation (K+ channels close) 3. voltage gated Ca++ channels 4. rise in global levels in cytoplasm 5. pressure induced constriction

Question 28

how does a calcium spark lead to relaxation of a artery?

Answer 28

1. calcium spark 2. activation of calcium sensitive potassium channels (BK) 3. efflux of K+ from cell 4. membrane hyperpolarisation 5. inactivation of voltage dependent calcium channels 6. reduction in free cytoplasmic calcium 7. relaxation

Question 29

what is meant by spontaneous transient outward currents (stoc)?

Answer 29

the outward movement of K+ due to the calcium sparks through BK channels (calcium-sensitive K+ channels) each upward deflection is the calcium spark activating about 30 adjacent BK channels, which then open and K+ leaves down its conc grad, measured as an upward deflection

Question 30

what are the 2 different pathways triggered by intraluminal pressure?

Answer 30

- constriction and vasodilatory pathways

Question 31

what happens when BK channels are pharmacologically switched off?

Answer 31

the artery constricts - no efflux of K+ from cell - depolarisation - activation of voltage gated Ca++ channels - increase in free cytoplasmic calcium - constriction

Question 32

what do we say BK channels are like at baseline?

Answer 32

switched on

Question 33

what are the 2 opposing forces present in arteries?

Answer 33

- main force = constriction in response to pressure | - vasodilation from Ca spark induced BK channel hyperpolarisation

Question 34

what happens if the vasodilation from Ca spark induced BK channel hyperpolarisation is lost?

Answer 34

- increased constriction of resistance arteries - loss of local auto regulation and hypertension - MICROVASCULAR DISEASE

Question 35

name some endothelial things regulated by intracellular Ca++ levels

Answer 35

- barrier function - release of NO - release of prostaglandins - release of hyperpolarising/dilating factors (EDHF)

Question 36

describe 3 different vasodilatory pathways

Answer 36

1. release of nitric oxide 2. release of prostacyclin (COX pathway) 3. endothelial dependent hyperpolarisation (EDH) predominately = vasodilatory function

Question 37

what is the role of of endoplasmic (endothelial) and sarcoplasmic (myocyte) reticulum?

Answer 37

store of calcium — when they release calcium, it activates adjacent calcium-activated K+ channels to cause an efflux of K+ out of the cell

Question 38

calcium spark vs. calcium pulsar

Answer 38

- CALCIUM SPARK — this is the calcium release event from SR in the vascular smooth muscle cell. sensitive to intraluminal pressure. activates the calcium-activated K+ channel to cause an efflux of K+ — reduces membrane depolarisation - CALCIUM PULSAR = Ca++ signals release from ER in endothelial cell — activates calcium-activated K+ channels — hyperpolarises endothelial cell — this hyperpolarisation is directly d=transmitted through to the vascular smooth muscle cell

Question 39

through what channels in the membrane of the SR does Ca++ leave?

Answer 39

Ryanodine Receptor (RyR)