Ramchandra: Regulation of Vascular Function

Question 1

What is the normal cardiac output at rest?

Answer 1

5L/min

Most of the cardiac output goes to the kidneys, liver, muscle and brain.

Question 2

What is the cardiac output of an individual during exercise? How does it increase?

Answer 2

25L/min - increased through increased heart rate as well as stroke volume, the second due to the frank starling law

Most of the cardiac output goes to the skin and muscles. Percentage of CO going to the brain drops but the volume stays the same. Drop caused by the increased CO.

Muscle - Increased O₂ for increased ATP generation.

Skin - Increased blood flow to release heat; reducing protein damage.

Question 3

What is the consequence of constant ultramarathon running?

Answer 3

Increased periods of reduced internal organ perfusion leading to internal organ damage.

Question 4

How does the innervation vary across the vascular tree?

Answer 4

Sympathetic Nerves supply all of the vascular beds. However, arteries and arterioles are densely innervated, whereas the veins are more sparsely innervated.

Innervation of the veins increases as the vessel size increases.

Capillary beds receive no direct innervation.

Question 5

How do blood vessel dimensions change?

Answer 5

Smooth Muscle Cells that surround the endothelium of the capillaries contract when stimulated by sympathetic nerves.

The highest proportion of vascular smooth muscle found in small arteries and arterioles.

Question 6

How does vasoconstriction affect pressure?

Answer 6

Vasoconstriction increases the precapillary resistance and therefore blood flow is reduced.

• However, this also leads to a greater dissipation of energy as blood flows through the small arteries and arterioles.
• This further leads to an increased pressure gradient and therefore reduced hydrostatic pressure in the capillaries.

Postcapillary constriction can occur to some level but is not as effective as precapillary

Question 7

What is autoregulation?

Answer 7

This is where perfusion pressure is altered to a specific organ and the neural input is ablated. It uses constriction to adjust the flow in order to counteract pressure changes. (eg. if pressure increases then the precapillary vessels constrict allowing less flow thus returning perfusion to its constant)

• Acute Reduction in Perfusion Pressure = Increase to constant over time.
• Acute Increase in Perfusion Pressure = Decrease to constant over time.

Question 8

What is reactive hyperaemia?

Answer 8

This is the phenomenon that demonstrates the link between metabolism and blood flow. It occurs after a blood vessel is occluded for a short period. When the occlusion is released, blood flow rises above the pre-occlusion level and this hyperaemia is maintained for a period roughly proportional to the duration of the occlusion.

Question 9

What is the myogenic hypothesis?

Answer 9

Is linked to the understanding/explanation of autoregulation

• Increased perfusion pressure increases vascular pressures throughout the circulation.
• Increased transmural pressure leads to vascular distension.
• Stretch elicits smooth muscle contraction.

Question 10

What is the metabolic hypothesis of local control?

Answer 10

If a given organ is working harder it will demand more flow and cause vasodilation of the arteries supplying it. It does this through release of metabolites that cause vasodilation.

• For Example: If the heart is asked to work harder (through an increase in heart rate) it will result in coronary vasodilation. In this example, the effects of norepinephrine that binds to alpha receptors causing vasoconstriction is overridden.

.

Question 11

What are the mediators of the metabolic hypothesis?

Answer 11

• Decreased pH - Especially in exercising muscle - lactic acid
• Increased potassium - As more ATP is utilised.
• Adenosine and Adenine Nucleotides.

Question 12

Where are the effects of the metabolites most strong?

Answer 12

The metabolites have their strongest effect in causing vasodilation in the terminal of the pre-capillary vessels but is limited in the post-capillary vessels.

The effects of these metabolites do not explain the coordinated vasodilation throughout pre-capillary distribution circuit

Question 13

How is NO formed?

Answer 13

Shear stress on vascular endothelium - caused by increased blood flow - leads to the catalysation of L-Arginine to citrulline and NO by NO synthase (endothelial form of the enz.)

Question 14

What are the two other integrative models?

Answer 14

• ATP released in microcirculation by red blood cells due to reduced pO₂ acts directly on endothelium.
• Electrically activated vasodilation conducted rapidly upstream via the endothelium.

Question 15

The diagram on the integrated model of local control…

Answer 15

Question 16

What occurs in postganglionic sympathetic nerves in response to their depolarization?

Answer 16

1. Calcium enters the nerve terminal via calcium channels.
2. Calcium causes vesicles containing norepinephrine to fuse to the nerve membrane,
3. Norepinephrine then released out into the synaptic cleft
4. It then binds to a receptor or difuses into the blood stream

Question 17

What is tyrosine hydroxylase?

Answer 17

This is an enzyme found in all postganglionic sympathetic nerves which act to convert tyrosine into DOPA and then dopamine.

Question 18

What do the postganglionic vesicles contain?

Answer 18

• Norepinephrine
• ATP
• Neuropeptide-Y
• Vasopressin

Question 19

What is the function of the norepinephrine released from the postganglionic sympathetic nerves?

Answer 19

• Binds to the postsynaptic receptors - Resulting in a conformational change of the postsynaptic cell.
• Binds to receptors on the nerve terminal itself - This acts to regulate the release of norepinephrine.
• Some washed off into the circulation.
• Some is metabolised.

Question 20

How do you influence the postsynaptic cell function?

Answer 20

• Increase or decrease the amount of sympathetic drive.

OR

• Increase or decrease the number of adrenoreceptors in the smooth muscle (postsynaptic cell).

Question 21

What are the two types of adrenoreceptors present in the postsynaptic cell?

Answer 21

• Alpha - 1
• Alpha - 2

Question 22

What happens when norepinephrine binds to the alpha-1 receptor?

Answer 22

1. Norepinephrine binds the surface receptor.
2. Activates G-protein q
3. Activates Phospholipase C
4. Phospholipase C cleaves PIP₂ into DAG and IP3.
5. DAG activates Protein Kinase C which leads to further protein phosphorylation.
6. IP3 leads to further release of intracellular Ca²⁺ .

Overall, causes increased cytoplasmic Ca²⁺ and therefore vasoconstriction.

Question 23

What occurs when norepinephrine binds to alpha-2 receptors?

Answer 23

1. Gi-Protein inhibits adenylate cyclase.
2. Leads to decreased cAMP production.
3. Leads to inactivation of Protein Kinase A.
4. Less phosphorylation of proteins.
5. Also, increases the activity outwardly flowing K+ channel which effectively hyperpolarizes the cell leading to vasodilation.

Overall, leads to a decrease in cytoplasmic Ca²⁺ leading to vasodilation.

Question 24

What are the inhibitory modulators of adrenergic neurotransmission?

Answer 24

• Acetylcholine
• Adenosine
• Dopamine
• Histamine
• Prostaglandin E₁ and E₂

Question 25

What are the excitatory modulators of adrenergic neurotransmission?

Answer 25

• Angiotensin II
• Adrenaline

Question 26

What is the function of Angiotensin II?

Answer 26

Binds to angiotensin receptors on the presynaptic nerve terminal causing increased fusion of vesicles to the membrane as well as stopping reuptake of NE leaving it in the cleft or longer. Therefore acts to increase/promote norepinephrine release.

Also has a role on the postsynaptic cell where it binds to alpha-1 receptors leading to vasoconstriction.

Question 27

Why are some individuals with hypertension given angiotensin blockers?

Answer 27

Angiotensin Blockers reduce norepinephrine release from the presynaptic terminal and decreases alpha-1 receptor activation on the postsynaptic cells.

Both act to reduce vasoconstriction and therefore lower blood pressure.

Question 28

What are cholinergic nerves?

Answer 28

The cholinergic innervation of blood vessels is largely parasympathetic. They lead to an increase in ACh which binds M₃ muscarinic receptors in the endothelium of blood vessels, stimulating nitric oxide release and therefore vasodilation.

Question 29

In the presence of vascular damage, how does ACh function?

Answer 29

In the presence of vascular damage, the ACh will bind directly to the muscarinic receptors in the vascular smooth muscle causing vasoconstriction.

Question 30

What occurs when noradrenaline is given to a patient?

Answer 30

Leads to vasoconstriction and therefore decreased…

• Skeletal Muscle Flow
• Skin Flow
• Kidney Flow
• Splanchnic Flow

Question 31

Where does noradrenaline not act?

Answer 31

• Cerebral Vessels - Unable to cross BBB.
• Coronary Vessels.

Question 32

What occurs if adrenaline is given to a patient?

Answer 32

Leads to increased…

• Skeletal Muscle Flow
• Splanchnic Flow

Leads to decreased…

• Skin Flow
• Kidney Flow

Question 33

What do the different outcomes caused upon infusion of noradrenaline vs adrenaline tell us about them?

Answer 33

Adrenaline has the same affinity for alpha-1 and alpha-2 receptors as noradrenaline but there is a change in alpha-1 adrenoreceptors expression in the skeletal muscle and splanchnic organs. (where for adrenaline the splanchnic and Sk. muscle vasodilates )

or

That the affinity is different for the two.

Question 34

Is beta-2 receptor outcomes similar to alpha-1 or alpha-2 receptors?

Answer 34

Beta-2 receptor action has similar outcomes to alpha-2 actions. This is because it ultimately results in the production of protein kinase A and therefore vasodilation.

Question 35

What are the differences in affinity for alpha and beta-2 receptors?

Answer 35

Question 36

What are the effects of an increased sympathetic drive on an individual at rest in comparison to during exercise?

Answer 36

At rest, an increased sympathetic drive can have profound effects on the blood flow - and thus cardiac output - to the skeletal muscle. However, during exercise, this increase in sympathetic drive does not have nearly the same effect due to it being overriden by metabolic vasodilation (pirmarily seen in skeletal muscles with high metabolite production)

Question 37

What causes the profound vasodilation during exercise?

Answer 37

• Increased Circulating Levels of Adrenaline.
• Histamine release causes relaxation of pre-capillary vessels and inhibits sympathetic neurotransmission.
• Increased perivascular concentrations of vasodilator metabolites act to relax smooth muscle and inhibit sympathetic adrenergic neurotransmission.

Question 38

What are the effects of vascular function on the skin’s circulation?

Answer 38

The affinity of alpha-receptors in the skin for noradrenaline decrease with a rise in local temperature and vice versa. As well as this, there is greater sympathetic cholinergic innervation in the skin. This cholinergic innervation activates the sweat glands leading to release of the enzyme kallikrein, which activates the kinin cascade.

The bradykinin and lysylbradykinin produced acts to dilate the precapillary vessels, constrict postcapillary vessel and increase capillary permeability.

• We essentiall will never not be able to supply the skins demands and so the flow is rather determined by heat through the sympathetic system than by metabolic control

Question 39

What is the relationship between pressure and flow in cerebral circulation?

Answer 39

Has to maintain a constant flow so expresses autoregulation between the perfusion pressures of 60 - 180 mmHg.

• This isn’t completely accurate as there are small changes witnessed in acute pressure changes. This is important to remember in our clinical career.

Question 40

What regulates cerebral circulation?

Answer 40

Cerebral circulation is regulated by a number of local factors. This includes perivascular pH, pCO₂, pO₂ and (K⁺) which are all important vasodilator metabolites.

• P_aCO₂ < 40 mmHg = Vasoconstriction
• P_aCO₂ > 40 mmHg = Vasodilation
• P_aO2 < 50 mmHg = Vasodilation

The response of Bflow to Partial Pressure of oxygen is far less steep compared to the response to changes on CO2 PP

Question 41

What determines blood flow to the heart?

Answer 41

Blood Flow to the heart nearly purely under the control of metabolic vasodilation. As a result, as the heart works harder (increased HR) you get vasodilation due to an increase in the release of metabolites.