Manipulation of Vascular Tone

Question 1

Identify the three main classes of cell surface receptors

Answer 1

Ion-channel/ligand-gated
Ion-channel, neurons
Ligand-gated, peptides
E.g. angiotensin-II, Vasopressin

G-protein-linked
Pheromones
Hormones
Neurotransmitters
cAMP, IP3

Enzyme-linked
Transmembrane element
Activates intracellular enzyme
e.g insulin (tyrosine kinase)

It is important as it helps to determine how drugs, hormones etc work. How quickly they become effective, and how quickly they are cleared from the system

Question 2

Describe how hydrophobic signaling factors can act directly at the nucleus

Answer 2

Hydrophobic drugs are carried through the blood using transport proteins. They are released at the cell membrane and are able to easily cross the lipid bilayer due to lipid soluble nature.

Once within the cell the drug is able to bind to proteins within the cytosol. These cytosolic proteins are known as heat-shock proteins (HSP).

They form a hormone-receptor complex causing conformational changes, allowing the complex to cross through the nuclear mebrane and release the receptor

The drug acts at the nucleus, causing transcription which leads to further hormone secretion

Steroid hormones act in this way

Question 3

Why is hormone (or drug) bound to transport protein in blood?

Answer 3

Lipid soluble so is transported by binding globulin proteins which are made in the liver.

Question 4

How can hormone (or drug) get across plasma membrane so easily?

Answer 4

Lipid soluble nature

Question 5

List examples of lipid soluble steroid hormones

Answer 5

Examples of steroid hormones:
Testosterone
Aldosterone
Thyroid
Cortisol etc…

Question 6

Describe how hydrophilic signaling factors can act at the cell surface

Answer 6

Water soluble proteins are unable to cross the lipid bilayer without help. Therefore most use an intracellular second messenger system

The signal molecule binds to a receptor protein (which is usually embedded in the plasma membrane), thereby activating an intracellular signaling pathway that is mediated by a series of signaling proteins.

Finally, one or more of these intracellular signaling proteins interacts with a target protein, altering the target protein so that it helps to change the behavior of the cell.

All peptide hormones are water soluble

Question 7

Describe the main ultrastructural features of a vascular smooth muscle (VSM) cell

Answer 7

Actin filaments

Gap junctions

Myosin

Sarcoplasmic reticulum

Question 8

Describe the functional role of VSM cells

Answer 8

The VSM cells form a functional syncytium where they undergo coordinated vasoconstriction and coordinated vasodilation

Question 9

State the roles of the principal ion channels governing VSM tone

Answer 9

Mostly used in veterinary medicine to control BP

Calcium channels (mediate contraction/dilation)
K channels (mediate hyperpolarisation)
Na/k ATPase (provides energy)

All are exploited pharmacologically to influence BP, alleviate end organ-damage, relax vascular smooth muscle, control heart rate etc…. Intracellular calcium is key

Question 10

List examples of endothelial derived factors that influence vasomotor tone and describe their cellular signaling mechanisms (local autocrine and paracrine control)

Answer 10

Endothelin (Endothelin receptors)
-G-protein coupled receptors (multiple second messenger systems)

Angiotensin II (AT2 receptors)
-G-protein coupled receptors (phospholipase C, protein kinase C, IP3; various according to site in body)

Norepinephrine//Epinephrine (alpha-adrenergic receptors)
-cell surface glycoprotein, cAMP (also IP3)

Nitric oxide
-eNOS, enzymatic-linked receptor, cGMP

Prostaglandins
-G-proteins, cAMP

Question 11

Explain how prostaglandin signalling manipulates vasomotor tone

Question 12

Explain how the RAAS system manipulates vasomotor tone

Question 13

Explain how Nitric Oxide manipulates vasomotor tone

Question 14

List the mechanisms that operate locally to regulate arteries and veins

Answer 14

Local blood

Basal State

Releasing metabolic factors

Question 15

Describe the importance of calcium in vasomotor regulation

Question 16

Describe how the mechanism of local blood flow regulates arteries and veins

Answer 16

Blood flow is determined by relative open/close state of arterioles, and so flow can be highly variable.

Poiseuille’s law describes how flow can be related to perfusion pressure, radius, length and viscosity of the blood.

Most important physiological reason would be vessel diameter in controlling blood flow, a very small change can produce large changes in resistance

Question 17

Describe how the mechanism of local basal states regulate arteries and veins

Answer 17

Capillaries basal state is less that 10% dilated

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Question 18

Describe how the mechanism of releasing metabolic factors regulate arteries and veins

Answer 18

In an area of low oxygen a build up of local metabolites occurs.

This leads to vasodilation to increase blood flow which is done by reactive hyperaemia which is the adjustment of blood flow to meet needs of tissues, by acting to remove the metabolites.

Local metabolites include pH, pO2, H+, K+, adenosine

In areas of chronic hypoxia vascular growth is stimulated by processes of angiogenesis (this often occurs in tumors)

Question 19

What is function hyperemia?

Answer 19

process by which blood flow is adjusted to meet metabolic needs of different tissues during a functional demand such as exercise