Lecture 08 Vascular Physiology 2

Question 1

In what diseases is the vascular targeted in treatment?

Answer 1

hypertension
heart failure
angina
pulmonary hypertension
Raynaud's syndrome

Question 2

What is the pathophysiology and epidemiology of hypertension?

Answer 2

high blood pressure
affects around 30% people in England
untreated can lead to increased risk of MI or stroke

Question 3

What are the symptoms of hypertension?

Answer 3

breathlessness
fatigue
fluid retention

Question 4

What are the causes of hypertension?

Answer 4

atherosclerosis
loss of glycocalyx
calcification
loss of elastin from vasculature
decreased NO - diet, smoking and hypoxia

Question 5

What is the impact and risks of a high sodium diet?

Answer 5

reduces NO - damaged glycocalyx and increased endothelin-1 production
loss of vasodilation and hypertension

Question 6

What is the pathophysiology of heart failure?

Answer 6

inadequate CO to meet metabolic demand
disease of heart itself
secondary to IHD, atherosclerosis and/or MI

Question 7

What is the pathophysiology of angina?

Answer 7

the oxygen supply to the heart is insufficient upon exertion, leading to chest pain
often as a result of IHD

Question 8

What is the pathophysiology of pulmonary hypertension?

Answer 8

narrowing of the pulmonary arteries causing increased pressure on the right side of the heart (right heart failure)
life expectancy 1-3 years from diagnosis

Question 9

What is the pathophysiology of Raynaud’s disease?

Answer 9

inappropriate vasoconstriction of smaller arteries/arterioles

Question 10

What are the symptoms of Raynaud’s?

Answer 10

white then blue fingers, then red as blood flow returns

ulceration and gangrene (severe)

Question 11

What causes Raynaud’s disease?

Answer 11

spasms of the arteries leading to reduced blood flow

over-activation of sympathetic NS leading to extreme vasoconstriction

Question 12

What are treatments for Raynaud’s?

Answer 12

stopping smoking (increased risk in smokers)
avoiding cold 
vasoactive therapies

Question 13

What are the two types of Raynaud’s?

Answer 13

Primary - idiopathic (unknown cause, maybe hereditary)
Secondary - associated with connective tissue disorders, obstruction (atherosclerosis) and some drug side effects (beta-blockers and chemotherapy)

Question 14

Name 4 endothelial mediators that regulate VSMC contractility
What does each mediator lead to?

Answer 14

nitric oxide - vasorelaxation
prostanoid - vasorelaxation and contraction
endothelin - vasocontraction
angiotensin II - vasocontraction

Question 15

How is the NO pathway targeted?

Answer 15

NO donors can be converted into NO by mitochondrial aldehyde dehydrogenase

Question 16

Give examples of NO donors and when they are used

Answer 16

nitroglycerine - angina and IHD
sodium nitroprusside - emergency hypertension
inhaled NO - severe pulmonary hypertension

Question 17

What treatments are given to potentiate vasorelaxation via the prostanoid pathway?
What do these treatments do?
When are they used?

Answer 17

corticosteroids - suppress formation of prostaglandins - prevent shock and hypotension
iloprost - PGI2 stable analogue potentiating relaxation pathway - pulmonary hypertension, Raynaud’s
epoprostenol - IP receptor agonist - sometimes pulmonary hypertension

Question 18

What treatments are given to potentiate vasorelaxation via the endothelin pathway?
What do these treatments do?
When are they used?

Answer 18

Phosphoramidon - ECE inhibitor preventing ET-1 production - experimental tool
Bosentan - ET-alpha/ET-beta inhibitor - pulmonary hypertension (phase 3 clinical trials for ischaemic optic neuropathy)

Question 19

What treatments are given to potentiate vasorelaxation via the angiotensin pathway?
When are they used?

Answer 19

ACE inhibitors - captopril and enalapril - hypertension, heart failure, post-MI
AT1 receptor antagonists - sartans - reduce blood pressure

Question 20

Give an example of an ACE inhibitors
What does this treatments do?
What are the side effects?

Answer 20

captopril
blocks the ACE enzyme site
hypotension, cough, proteinuria, changes to taste

Question 21

Give examples of Sartans

What does this treatment do?

Answer 21

Losartan and Valsartan

antagonise the AT-1 receptor and inhibit production of angiotensins in the renin-angiotensin-aldosterone system

Question 22

Describe the angiotensins

Answer 22

angiotensins I-Iv are derived from the precursor protein angiotensinogen N-terminal
renin converts angiotensinogen into angiotensin I
renin is secreted from kidney into the blood circulation

Question 23

What was the problem with sympathetic NS acting drugs?

Answer 23

too many (multiple) or severe side effects

Question 24

Give examples of VSMC directly acting therapies

What do they treat?

Answer 24

calcium channel blockers
nifedipine - hypertension, Raynaud’s, angina
verapamil - hypertension, heart failure
dilitiazem - hypertension, angina

potassium channel activators
minoxidil - severe hypertension (hair loss)
diazoxide - severe hypertension
nicorandil - refractory angina

PDE inhibitors
PDE V inhibitor - sildenafil - pulmonary hypertension

Question 25

What can’t be used in combination with PDE inhibitors? Why?

Answer 25

NO donors (nitroglycerin) and angina therapies
combination causes severe drop in blood pressure

Question 26

How do PDE inhibitors work?

Answer 26

hydrolyse cAMP and cGMP leading to activation of PKA and PKG (respectively) leading to potentiation of myosin phosphatase and muscle relaxation