Pharmacology: Drugs on Vascular Smooth Muscle

Question 1

Define vascular tone.

Answer 1

Vascular tone is the degree of constriction of a blood vessel relative to maximum dilation.

Question 2

Explain how vascular tone ultimately determines organ perfusion.

Answer 2

Vascular tone controls blood vessel radius > controls resistance > controls pressure and flow > determines perfusion.

Question 3

Name the 5 main vasoconstrictor agents and explain their mechanisms of action, including their receptors.

Answer 3

Noradrenaline: released from sympathetic nerves – acts at α1-adrenoceptors on VSMCs.

Adrenaline: released from adrenal medulla – at high enough concentrations will act on α1-adrenoceptors. Remember - most vascular beds do not contain many β2-adrenoceptors.

Angiotensin II: formed from RAAS, acting on AT1 receptors on VSMCs.

Vasopressin (ADH): released from posterior pituitary,
acting on V1-receptors on VSMCs.

Endothelin-1: released from the endothelium, acts on ETA receptors on VSMCs.

Question 4

Excess production of vasoconstrictor agents is associated with which cardiovascular conditions?

Answer 4

Hypertension and heart failure.

Question 5

Explain the cellular mechanism by which vasoconstrictor agents increase vascular tone.

Answer 5

1. All receptors are Gq/11 linked.
2. Gq activates phospholipase C.
3. PLC breaks down PIP2 into IP3 and DAG.
4. IP3 binds to IP3 receptors on the sarcoplasmic reticulum, causing Ca2+ efflux into cytosol. Intracellular Ca2+ is increased.
5. DAG increases membrane excitability, enhancing activation of VGCCs.
6. Activation of VGCCs leads to Ca2+ influx into VSMC, causing contraction.

Question 6

Explain the mechanism by which a rise in intracellular Ca2+ leads to smooth muscle contraction.

Answer 6

1. Ca2+ activates calmodulin, forming a Ca2+-calmodulin complex.
2. This complex activates MLCK.
3. MLCK phosphorylates MLC, thereby activating the myosin ATPase.
4. This allows the formation of actin-myosin cross-bridges and consequently contraction.

Question 7

Which enzyme found in VSMCs reduces contraction?

Answer 7

Myosin light chain phosphatase (MLCP).

Question 8

Name the 5 main vasodilator agents, treating the class of inflammatory mediators as a single agent. Explain their mechanisms of action, including their receptors.

Answer 8

Adrenaline: acting at β2-adrenoceptors found in some vascular beds, e.g. skeletal muscle, coronary.

Nitric Oxide (NO): synthesised in endothelium, released and acts on VSMCs (also prevents platelet aggregation)

Prostacyclin (PGI2): released from endothelium, acts on VSMCs to activate PKA pathway to produce vasodilation (also inhibits platelet aggregation).

Inflammatory mediators, e.g. histamine, bradykinin, PGE2, Sub P: act on endothelium to produce NO which produces vasodilation.

K+ ions: released from endothelium, neurones, skeletal/cardiac muscle contraction - produces hyperpolarisation of VSMCs, vasodilation. Correlates metabolic activity of tissue to blood flow (metabolic hyperaemia).

Question 9

Excess production of vasodilator agents is associated with what cardiovascular conditions?

Answer 9

Dangerous hypotension, poor blood flow, end organ damage - e.g. in sepsis.

Question 10

Decreased production of vasodilator agents due to endothelium dysfunction can cause what symptom?

Answer 10

Hypertension

Question 11

What is metabolic hyperaemia?

Answer 11

Increased blood flow to metabolically active tissues due to increased vasodilation - triggered by adenosine.

Question 12

Explain the cellular mechanism by which vasodilator agents decrease vascular tone.

Answer 12

All vasodilator agents decrease VSMC contraction by blocking receptors coupled to Gq/11, which decreases [Ca2+]i. Blocking these receptors leads to the following effects:

1. Increased SERCA activity - more Ca2+ uptake into SR.
2. Increased PMCA activity - more Ca2+ extrusion from cell.
3. Increased K+ channel activity - hyperpolarisation.
4. Decreased membrane excitability.
5. Decreased MLCK and increased MLCP.

Question 13

Stimulation of β2-adrenoceptors on VSMCs

(coronary, skeletal muscle arteries) produces relaxation and therefore vasodilation. Explain how.

Answer 13

Gs pathway activates PKA, which has the following effects via phosphorylation:

1. Increased SERCA activity - more Ca2+ uptake into SR. 2. Increased K+ channel activity - hyperpolarisation - reduced VGCC activity.
2. PKA directly inhibits MLCK.
3. Also, decreased MLCK due to reduced [Ca2+]i.

Question 14

Activation of PKG has similar effects to activation of PKA. Name 2 receptors that produce PKG activation when stimulated and explain the mechanism by which PKG is activated.

Answer 14

1. ANP receptor.
2. NO receptor.

Both receptors activate guanylate cyclase when stimulated, which converts GTP to cGMP - cGMP then activates PKG.

Question 15

Why does depolarisation of vascular endothelial cells not cause calcium influx?

Answer 15

Endothelial cells do not have VGCCs - Ca2+ influx is through other channels.

Question 16

Vascular tone is mainly controlled by the balance of which two antagonistic processes?

Answer 16

1. Sympathetic activity - constriction.

2. No release - dilation.

Question 17

How do inflammatory mediators such as bradykinin, histamine and Substance P produce vasodilation? Refer to the location of the receptors involved.

Answer 17

Stimulation of receptors on endothelial cells activates Gq/11 pathway - eventually resulting in increased [Ca2+]i. This produces Ca2+-calmodulin, which stimulates eNOS (endothelium nitric oxide synthase) to produce NO. NO causes vasodilation via PKG and K+ channels.

Question 18

Nitric oxide stimulates vasodilation by directly activating what ion channel?

Answer 18

K+ channel activation - causing hyperpolarisation > reduced VGCC conduction.

Question 19

How does nitric oxide produced in the vascular endothelium exert its effects on VSMCs?

Answer 19

NO diffuses from the endothelium to VSMCs. It is a freely diffusible, lipophilic, soluble gas.

Question 20

Give an example of a VGCC blocker (CBB) used to treat hypertension and angina.

Answer 20

Amlodipine

Question 21

Glyceryl trinitrate (GTN) is used to treat angina and pulmonary oedema. Explain how its mechanism of action achieves VSMC relaxation.

Answer 21

GTN is metabolised to produce NO, which acts on VSMCs by activating guanylate cyclase. GTN is therefore known as an “NO donor”. This pathway leads to the activation of PKG, which activates MLCP. Overall PKG has effects which lead to relaxation, causing vasodilation.

Question 22

Name 3 α1-adrenoceptor antagonists and explain why they are used to treat hypertension.

Answer 22

Prazosin, doxazosin, phentolamine.

These drugs inhibit the action of vasoconstrictor agents that bind to the α1-adrenoceptor - noradrenaline and adrenaline. This prevents sympathetic nerve-induced vasoconstriction.

Question 23

Losartan is an antagonist of which receptor? Consequently, what is its physiological effect?

Answer 23

Losartan is an angiotensin II receptor antagonist. It binds to the AT1 receptor, competitively inhibiting stimulation of the receptor by angiotensin II. This prevents receptor-mediated vasoconstriction via the Gq/11 pathway. Thus, losartan is used to treat hypertension and heart failure.

Question 24

Viagra is used to treat erectile dysfunction. Explain its mechanism of action.

Answer 24

Viagra is a phosphodiesterase inhibitor - specifically PDE5, which is found in the corpus cavernosum of the penis. PDE5 breaks down cGMP. By inhibiting the breakdown of cGMP, viagra increases activation of PKG, which ultimately stimulates relaxation of vascular smooth muscle and therefore vasodilation. This results in increased blood flow to the penis and therefore reverses erectile dysfunction.

Question 25

Name a K+ channel opener that is used to treat angina.

Answer 25

Nicorandil

Question 26

Name an ACE inhibitor and explain how it benefits patients with hypertension and heart failure.

Answer 26

Enalapril - inhibits angiotensin-converting enzyme (ACE), preventing formation of angiotensin II from angiotensin I. Angiotensin II is a vasoconstrictor agent, therefore ACE inhibitors prevent AT1 receptor-mediated vasoconstriction.