L8 - Physiology of the Vasculature II

Question 1

What 5 diseases are there where we target the vasculature to treat them?

Answer 1

Hypertension
Heart Failure
Angina
Pulmonary Hypertension
Raynaud syndrome

Question 2

How does smoking damage vascular function?

Answer 2

Damages endothelial glycocalyx –> adhesion molecules exposed –> monocytes/neutrophils bind to endothelial cells –> initiate atherosclerosis
Nicotine causes adrenaline release –> artery contraction
Causes eNOS uncoupling in endothelial cells –> less NO production

Question 3

How does diabetes damage vascular function?

Answer 3

Impairs eNOS –> less NO production
Increased inflammation - ↑ endothelin/cytokine production
Net result - vasoconstriction

Question 4

How does obesity damage vascular function?

Answer 4

Fatty plaque –> physical separation between endothelial cells and VSMCs
NO cannot reach smooth muscle –> no arterial relaxation

Question 5

How does ageing damage vascular function?

Answer 5

Increased BP 
Impaired arterial relaxation 
- Fibrosis 
- Calcification - stiffens arteries 
- VSMCs become senesce - can undergo apoptosis 
- Elastin fragmentation

Question 6

How does infection damage vascular function?

Answer 6

Immune response –> activates endothelium –> recruitment of leukocytes to artery wall
Weakens atherosclerotic plaque - ↑ vulnerable to rupture
These stimuli generally activate pathways –> VSCM contraction

Question 7

Does smoking, diabetes, obesity and ageing cause vasculature to be more contracted or relaxed?

Answer 7

Contracted –> hypertension

Question 8

Hypertension overview

Answer 8

Affects around 30% of people in England
If left untreated, it increases a person’s risk of a heart attack or stroke
Commonly secondary to atherosclerosis

Question 9

Symptoms of hypertension

Answer 9

Breathlessness
Fatigue
Fluid retention
Overall cardiac output is not adequate to meet metabolic demands

Question 10

Heart failure overview

Answer 10

Inadequate cardiac output to meet metabolic demand

Disease of heart itself

Question 11

Causes of heart failure

Answer 11

Secondary to Coronary Artery Disease and/or myocardial infarction
Viral infections causing inflammation of the heart tissue
Kidney failure
Sleep apnea

Question 12

Angina overview

Answer 12

Oxygen supply to heart insufficient upon exertion
Leads to chest pain
Stable angina - if it does not worsen and only occurs upon exercise
Unstable – becomes progressively worse

Question 13

Causes of angina

Answer 13

Due to coronary artery disease/atherosclerosis

Question 14

Pulmonary hypertension overview

Answer 14

Narrowing of pulmonary arteries
Due to overgrowth of endothelial cells or VSMCs
↑ pressure on right side of heart → right heart failure
Life expectancy usually 1-3 years from diagnosis

Question 15

What is Raynauds disease?

Answer 15

Over-activation of sympathetic nervous system –> inappropriate vasoconstriction of smaller arteries/arterioles

Question 16

Symptoms of Raynauds disease

Answer 16

White then blue then redness on fingers/feet
- Reactive hyperaemia - return of blood flow
Severe cases - ulceration and gangrene
Spasm of arteries, leading to reduced blood flow

Question 17

Treatments for Raynauds disease

Answer 17

Stop smoking
Avoid cold
Vasoactive therapies

Question 18

Primary Raynauds

Answer 18

If idiopathic
May be somewhat hereditary
Increased risk in smokers

Question 19

What is secondary Reynauds associated with?

Answer 19

Connective tissue disorders
Obstruction (atherosclerosis)
Some drug side effects (beta blockers, chemotherapy)

Question 20

How do healthy endothelial cells relax?

Answer 20

Activated by high shear blood flow
Get activation of eNOS
Mediators (Ach, 5-HT) activate GPCRs –> IP3 –> increase Ca –> increased activation of eNOS –> relaxation

Question 21

How do activated endothelial cells contract?

Answer 21

Activated by IL-1 and thrombin –> activate endothelin 1 and ROS –> increased exposure of adhesion molecules on cell surface – capture circulating leucokyctes –> link to atherosclerosis –> constriction

Question 22

What are the two places Ca is stored and released from during VSMC contraction?

Answer 22

Plasma membrane

Sarcoplasmic reticulum

Question 23

How do second messengers lead to the release of SR Ca during VSMC contraction?

Answer 23

Second messengers released through activating G proteins –> IP3 –> release of Ca for SR

Question 24

What are the 3 mediators regulating VSMC relaxation?

Answer 24

Guanylyl cyclase –> cGMP –> decreased Ca
Adenylyl cyclase –> cAMP –> decreased Ca
K channels –> hyperpolarisation –> opposes Ca influx
Overall prevents contraction response by preventing Ca release - muscle relaxation

Question 25

How does NO play a role in VSMC relaxation?

Answer 25

NO released from endothelial cells Activates guanylyl cyclase --> cGMP Activates PKG --> activates myosin phosphatase --> more inactive myosin

Question 26

How do Gs couples receptors play a role in VSMC relaxation?

Answer 26

Activate adenylyl cyclase --> cAMP

Question 27

How do PDE enzymes oppose VSMC relaxation?

Answer 27

Break down cGMP and cAMP

Question 28

What are the 3 examples of NO donors used as treatment?

Answer 28

Nitroglycerine Sodium Nitroprusside Inhaled NO

Question 29

What does nitroglycerine treat?

Answer 29

Angina - ↑ blood flow to ischaemic heart muscle Nitroglycerine converted to NO by mitochondrial aldehyde dehydrogenase Used sublingually or as oral spray – rapidly effect/conversion to NO

Question 30

What does sodium nitroprusside treat?

Answer 30

Emergency hypertension

Question 31

What does inhaled NO treat?

Answer 31

Pulmonary hypertension (severe)

Question 32

What are the 3 examples of prostanoids used as treatment?

Answer 32

Iloprost Epoprostenol Corticosteroids

Question 33

What does iloprost treat?

Answer 33

Prostacyclin stable analogue Pulmonary hypertension Raynaud syndrome

Question 34

What does epoprostenol treat?

Answer 34

IP receptor agonist | Some uses in Pulmonary Hypertension

Question 35

What do corticosteroids treat?

Answer 35

Suppress formation of prostaglandins Prevents shock (hypotension) Long term use not recommended – can suppress immune system broadly

Question 36

What are the 2 examples of endothelin inhibition used as treatment?

Answer 36

Phosphoramidon | Bosentan

Question 37

What does phosphoramidon treat?

Answer 37

Endothelin Converting Enzyme inhibitor | Experimental tool

Question 38

What does bosentan treat?

Answer 38

Pulmonary Hypertension | Blocks both endothelin A and B receptors

Question 39

What are the two approaches to target angiotensin II to get a relaxation response?

Answer 39

Target - Production of angiotensin II - Activation of angiotensin II at AT1 receptor

Question 40

What are the 5 examples of targeting angiotensin II used as treatment?

Answer 40

``` AT1 receptor antagonists - Sartans – Losartan and Valsartan ACE inhibitors - Captopril - Enalapril and lisinopril ```

Question 41

What does losartan and valsartan treat?

Answer 41

Blood pressure reduction Also inhibit production of angiotensin at Renin-Angiotensin-Aldosterone system - Angiotensin I produced in the kidney

Question 42

What does captopril treat?

Answer 42

Hypertension, heart failure, after myocardial infarction | Blocks active site of enzyme

Question 43

What are the side effects of captopril?

Answer 43

Hypotension Cough Proteinuria Taste

Question 44

What does enalapril and lisinopril treat?

Answer 44

Hypertension, heart failure, after myocardial infarction Require conversion to active metabolite Longer acting

Question 45

What are the 3 types of directly acting therapies?

Answer 45

Ca channel blockers KATP channels activators PDE inhibitors

Question 46

What are two examples of Ca channel blockers?

Answer 46

Nifedipine | Verapamil

Question 47

What are 3 examples of KATP channel activators?

Answer 47

Minoxidil Diazoxide Nicorandil (NO donor)

Question 48

What are 2 examples of PDE inhibitors?

Answer 48

Sildenafil = Viagra | Tadalafil

Question 49

What do minoxidil and diazoxide treat?

Answer 49

Severe hypertension

Question 50

What does nicorandil treat?

Answer 50

Refractory angina

Question 51

Which treatment type should not be taken in combination with NO donors?

Answer 51

PDE inhibitors | As they can cause a severe drop in blood pressure

Question 52

Why are many sympathetic nervous system-acting drugs effective in hypertension now rarely used?

Answer 52

Multiple or severe side-effects

Question 53

What are the 5 drugs used to treat hypertension?

Answer 53

``` Sodium nitroprusside ACE inhibitors Sartans Nifedipine, verapamil Minoxidil, diazoxide ```

Question 54

What are the 2 drugs used to treat heart failure?

Answer 54

ACE inhibitors | Verapamil

Question 55

What are the 3 drugs used to treat angina?

Answer 55

Nitroglycerine Diltiazem Nicrorandil

Question 56

What are the 4 drugs used to treat pulmonary hypertension?

Answer 56

Inhaled nitric oxide Iloprost Bosentan Sildenafil and Tadalafil

Question 57

What are the 3 drugs used to treat Raynauds syndrome?

Answer 57

Iloprost Nifedipine Sildenafil