PBL 6 - regulation of vascular tone via calcium signalling Flashcards
what do global cytoplasmic calcium levels determine?
contractility
what do localise calcium signals within the cytoplasm do?
activate nearby K+ channels to cause hyperpolarisation and thus vasodilation
how do we treat patients with small vessel disease of the kidney?
dialysis (bypass kidney)
how do we treat patients with small vessel disease of the eye?
use laser gun to photocoagualte the retina — burn away all the dysfunctional arteries
how do we treat patients with small vessel disease of the brain (eg. vascular dementia)?
no treatment — institutional care
what are 3 macro vascular complications of when small arteries don’t function properly?
- stroke
- heart disease
- peripheral vascualr disease
what are 3 micro vascular complications of when small arteries don’t function properly?
- diabetic retinopathy
- diabetic nephropathy
- diabetic neuropathy
describe the endothelial lining of blood vessels
- monolayer
- endothelial cells run parallel to flow
describe the vascular smooth muscle of blood vessels
- vascular smooth muscle cells wrap around the lumen of the artery
- constrict — lumen gets smaller
what separates the endothelial monolayer from the thick muscular wall?
internal elastic lamina
equation for mean BP
BP = CO x TPR
what determines whether a vascular smooth muscle cell constricts or relaxes?
it’s electrical membrane potential (their electrical activity)
what is the most numerous ion channel in the plasma membrane of vascular smooth muscle cells?
K+ channels
what happens when K+ channels open?
- K+ leaves the cell as an intracellular ion
- hyperpolarisation — cell becomes more -ve
what happens when K+ channels close?
- inside of cell becomes more +ve = depolarisation
in what layer are smooth muscle cells located?
tunica media
describe a cross section of a blood vessel wall
- endothelium
- tunica intima
- IEM
- tunica media — smooth muscle
- EEM
- tunica externa
how do changes in the membrane potential effect of the contractile of the artery?
by influencing the activity of voltage-dependent calcium channels
what happens when the MP is lowered to result in reduced contractility of the artery?
- 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
what is the link between K+ and vasodilation/vasoconstriction?
K+ channels open = K+ leaves cell = vasodilation
K+ channels close = K+ doesn’t leave cell = vasoconstriction
what is the main channel that significantly impacts the resting tone of the small artery?
large conductance calcium-activated K+ channel = BKca
describe large conductance calcium-activated K+ channels (BKca)
- voltage dependent
- activated by small, very high concentrations of Ca++ — calcium release events from the sarcoplasmic reticulum
what causes contraction of arteries?
pressure — don’t contract and relax, just squeeze
how does pressure affects arterial Ca++ and hence lead to constriction?
increase in pressure = increase in arterial Ca++
- increase in intraluminal pressure
- artery stretches
- senses Ca++ in cytoplasm
- contractile process so therefore the artery squeezes
what happens if a drug blocks the voltage-gated Ca++ channels?
- no rise in arterial Ca++
- when the artery is stretched, it doesn’t constrict
describe the dual role of Ca++
- the global level of Ca++ determines how hard the artery squeezes
- Ca++ is released by the vascular smooth muscle endoplasmic/sarcoplasmic reticulum as small ‘release events’ = calcium sparks — activated the K+ channels to cause hyperpolarisation
describe how intraluminal pressure leads to pressure induced constriction
- intraluminal pressure
- membrane depolarisation (K+ channels close)
- voltage gated Ca++ channels
- rise in global levels in cytoplasm
- pressure induced constriction
how does a calcium spark lead to relaxation of a artery?
- calcium spark
- activation of calcium sensitive potassium channels (BK)
- efflux of K+ from cell
- membrane hyperpolarisation
- inactivation of voltage dependent calcium channels
- reduction in free cytoplasmic calcium
- relaxation
what is meant by spontaneous transient outward currents (stoc)?
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
what are the 2 different pathways triggered by intraluminal pressure?
- constriction and vasodilatory pathways
what happens when BK channels are pharmacologically switched off?
the artery constricts
- no efflux of K+ from cell
- depolarisation
- activation of voltage gated Ca++ channels
- increase in free cytoplasmic calcium
- constriction
what do we say BK channels are like at baseline?
switched on
what are the 2 opposing forces present in arteries?
- main force = constriction in response to pressure
- vasodilation from Ca spark induced BK channel hyperpolarisation
what happens if the vasodilation from Ca spark induced BK channel hyperpolarisation is lost?
- increased constriction of resistance arteries
- loss of local auto regulation and hypertension
- MICROVASCULAR DISEASE
name some endothelial things regulated by intracellular Ca++ levels
- barrier function
- release of NO
- release of prostaglandins
- release of hyperpolarising/dilating factors (EDHF)
describe 3 different vasodilatory pathways
- release of nitric oxide
- release of prostacyclin (COX pathway)
- endothelial dependent hyperpolarisation (EDH)
predominately = vasodilatory function
what is the role of of endoplasmic (endothelial) and sarcoplasmic (myocyte) reticulum?
store of calcium — when they release calcium, it activates adjacent calcium-activated K+ channels to cause an efflux of K+ out of the cell
calcium spark vs. calcium pulsar
- 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
through what channels in the membrane of the SR does Ca++ leave?
Ryanodine Receptor (RyR)
