Lecture 8 Physiology of the Vasculature II

Question 1

How does atherosclerosis impact the ability of the endothelium to regulate vascular smooth muscle

Answer 1

As atheroma’s develop the endothelial cells become separated and further away from the VSMCs. This means that the artery wall less able to regulate itself hence often leading to hypertension. In addition VSMCs are triggered to proliferate in response to immune cell invasion. This causes them to lose adhesion to each other and no longer contract as effectively

Question 2

What can happen specifically to the endothelium as a result of a loss of the glycocalyx as a result of oxLDL

Answer 2

They can become hyper-responsive and more likely to release contractile mediators

Question 3

What happens as a result of calcification of the blood vessels in disease

Answer 3

The build-up of calcified deposits results in a stiffening of the artery. This makes it less able to contract and relax in a coordinated way

Question 4

Loss of which extracellular matrix protein in the vessel wall can also play a role in disease

Answer 4

Elastin

Question 5

Hypoxia uncouples eNOS T or F

Answer 5

T

Question 6

What is the evidence for the incidence of hypertension

Answer 6

Around 30% of people are affected in England

Question 7

What risk is massively increased in patients left untreated for hypertension

Answer 7

Increased risk of heart attack and stroke

Question 8

What is the leading risk factor for the overall global burden of disease

Answer 8

Hypertension

Question 9

What are the symptoms of hypertension

Answer 9

Breathlessness fatigue fluid retention as cardiac output not adequate to meet metabolic demands

Question 10

What is the most common cause of hypertension

Answer 10

Secondary to atherosclerosis

Question 11

Heart Failure is where there is an inadequate cardiac output to meet metabolic demand what is the most common cause of heart failure

Answer 11

Disease of heart itself secondary to coronary artery disease (atherosclerosis) and/or myocardial infarction

Question 12

Other than MI and atherosclerosis what else can cause heart failure

Answer 12

Severe viral infections kidney failure and sleep apnoea

Question 13

What is meant by angina

Answer 13

Angina is where the oxygen supply to the heart is insufficient upon exertion leading to chest pain

Question 14

What is the main cause of angina

Answer 14

Coronary artery disease

Question 15

What are the two types of angina and how do they differ

Answer 15

Stable angina is where symptoms present during exercise. On the other hand unstable angina is where the angina can occur in the absence of exertion and is often linked to other myocardial syndromes

Question 16

What is pulmonary hypertension

Answer 16

Pulmonary hypertension is where there is a narrowing of the pulmonary arteries. This is caused by proliferation of the vascular smooth muscle and endothelial cells

Question 17

What are the effects of pulmonary hypertension

Answer 17

Increased pressure in the lungs and in the right side of the heart. This often results in right sided heart failure

Question 18

What is the prognosis for patients with pulmonary hypertension

Answer 18

There is an extremely poor prognosis with patients usually surviving only 1-3 after diagnosis

Question 19

What is Raynaud’s disease

Answer 19

This is where there is an inappropriate vasoconstriction of smaller arteries/arterioles. This is most commonly seen in the hand and fingers

Question 20

How does Raynaud’s disease usually present

Answer 20

White then blue fingers when exposed to the cold. Then redness upon warming up (reactive hyperaemia return of blood flow)

Question 21

What happens in severe cases of Raynaud’s disease

Answer 21

It can cause ulceration and gangrene

Question 22

What are the risk factors for Raynaud’s disease

Answer 22

Smoking hereditary component connective tissue disorders

Question 23

What causes Raynaud’s disease

Answer 23

The spasms in the VSMCs of the arteries are due to an overactivation of the sympathetic nervous system

Question 24

Other than avoiding cold and smoking cessation what therapies are often administered to patients with Raynaud’s

Answer 24

Vasoactive therapies that promote vasodilation

Question 25

What are the 4 pathways by which the endothelium regulate the VSMCs and what is the effect of each

Answer 25

NO – relaxation angiotensin II – constriction prostanoids – constriction and relaxation endothelin – constriction

Question 26

What are the three drugs used to target the NO pathway and trigger vasodilation

Answer 26

Glyceryl trinitrate nitroprusside and inhaled NO

Question 27

Which NO donor is commonly used in angina and how does it act

Answer 27

Glyceryl trinitrate or nitroglycerine is an NO donor used in angina. It is administered as a rapid acting spray or dissolvable sublingual tablet. Nitroglycerine is rapidly converted to NO by mitochondrial aldehyde dehydrogenase where it can then stimulate guanylate cyclase

Question 28

Which NO donor therapy is often used in severe hypertension and hospital settings where is can be delivered intravenously

Answer 28

Nitroprusside

Question 29

Which NO therapy isn’t an NO donor and is used mainly in pulmonary hypertension and in the clinical setting

Answer 29

Inhaled NO

Question 30

What is the aim of prostanoid therapy with regard to the individual prostanoids involved

Answer 30

Prostanoid therapies try to block the TP-R receptor that is responsible for contraction of the vascular smooth muscle and stimulate the IP-R receptor that is responsible for relaxation

Question 31

What is the mechanism of action of Iloprost

Answer 31

Iloprost is a stable analogue of prostaglandin I2 that binds to the IP-R and increases cAMP

Question 32

What is the main indication for iloprost

Answer 32

Pulmonary hypertension and Raynaud’s disease

Question 33

What is the mechanism of action of Epoprostenol

Answer 33

Epoprostenol is an IP-R agonist that binds to the IP-R and increases cAMP

Question 34

What is the main indication for epoprostenol

Answer 34

Pulmonary hypertension

Question 35

What is the effect of corticosteroids on the prsotenoid pathway

Answer 35

Corticosteroids decrease COX2 transcription and hence suppresses the formation of prostaglandins. These are used to cause a vasoconstriction

Question 36

Why do we want to target drugs just for the ETA receptor in terms of vascular therapies

Answer 36

The endothelin receptor ETA is specific for vascular smooth muscle cells. A drug that was an agonist of this specific receptor wouldn’t have the negative feedback activity of the ETB receptor agonists. This would be able to cause a more substantial vasodilation

Question 37

Give an example of a vasoactive drug that targets the endothelin pathway

Answer 37

Bosentan is a drug that non-specifically blocks ETA and ETB receptors and causes vasodilation. It is used in the treatment of pulmonary hypertension

Question 38

When are ACE inhibitors often used

Answer 38

In hypertension and heart failure where this has occurred after myocardial infarction

Question 39

What is the mechanism of action of captopril

Answer 39

Captopril blocks the active site of the ACE enzyme

Question 40

What are the side effects of ACE inhibitors

Answer 40

Hypotension drug cough proteinuria and a change in taste perception

Question 41

What is the benefit of enalapril and lisinopril over captopril

Answer 41

These drugs require conversion to an active metabolite. They therefore are much longer acting drugs

Question 42

Give some examples of AT-1 receptor antagonists used in hypertension

Answer 42

Losartan valsartan

Question 43

Which enzyme cleaves angiotensinogen to angiotensin I

Answer 43

Renin released by the JGA of the kidney

Question 44

Which enzymes converts angiotensin I to angiotensin II

Answer 44

ACE

Question 45

Where is ACE specifically expressed

Answer 45

In the renal and lung endothelium

Question 46

Where is angiotensinogen produced

Answer 46

In the liver

Question 47

As well as targeting the endotheliums’ regulation of VSMCs what other target are there for therapies in vascular disease

Answer 47

Targets of the smooth muscle itself

Question 48

What are the opposing effects of adrenoceptor agonists in the vascular system

Answer 48

Noradrenaline acting on αARs causes IP3 production and contraction of the muscle. Meanwhile adrenaline acting on βARs stimulates adenylate cyclase and cAMP production causing relaxation

Question 49

Many sympathetic nervous system-acting drugs effective in hypertension now rarely used due to multiple or severe side-effects T or F

Answer 49

T

Question 50

Which Ca2+ channel blockers are used in hypertension

Answer 50

Nifedipine verapamil and diltiazem

Question 51

Which Ca2+ channel blockers are used in angina

Answer 51

Nifedipine and diltiazem

Question 52

Which Ca2+ channel blocker is used in Raynaud’s

Answer 52

Nifedipine

Question 53

Give some examples of K+ channel activators used in hypertension

Answer 53

Minoxidil diazoxide and nicorandil

Question 54

What is the additional benefit of nicorandil that makes it useful in the treatment of angina

Answer 54

As well as it opening K+ channels nicorandil is an NO donor and is therefore quite often used in refractory angina

Question 55

How can PDE be targeted in the treatment of pulmonary hypertension

Answer 55

PDE inhibitors can be a valuable therapeutic target in the treatment of vascular disease. Sildenafil the PDE V inhibitor inhibits the breakdown of cAMP and cGMP. This causes relaxation of the smooth muscle. Hence this treatment is used for pulmonary hypertension (as well as ED)

Question 56

What is the major contraindication of PDE inhibitors

Answer 56

They should never be used in conjunction with an angina treatment such as NO donors. This could dangerously reduce blood pressure in the patients