Lecture 08 Vascular Physiology 2 Flashcards
In what diseases is the vascular targeted in treatment?
hypertension heart failure angina pulmonary hypertension Raynaud's syndrome
What is the pathophysiology and epidemiology of hypertension?
high blood pressure
affects around 30% people in England
untreated can lead to increased risk of MI or stroke
What are the symptoms of hypertension?
breathlessness
fatigue
fluid retention
What are the causes of hypertension?
atherosclerosis loss of glycocalyx calcification loss of elastin from vasculature decreased NO - diet, smoking and hypoxia
What is the impact and risks of a high sodium diet?
reduces NO - damaged glycocalyx and increased endothelin-1 production
loss of vasodilation and hypertension
What is the pathophysiology of heart failure?
inadequate CO to meet metabolic demand
disease of heart itself
secondary to IHD, atherosclerosis and/or MI
What is the pathophysiology of angina?
the oxygen supply to the heart is insufficient upon exertion, leading to chest pain
often as a result of IHD
What is the pathophysiology of pulmonary hypertension?
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
What is the pathophysiology of Raynaud’s disease?
inappropriate vasoconstriction of smaller arteries/arterioles
What are the symptoms of Raynaud’s?
white then blue fingers, then red as blood flow returns
ulceration and gangrene (severe)
What causes Raynaud’s disease?
spasms of the arteries leading to reduced blood flow
over-activation of sympathetic NS leading to extreme vasoconstriction
What are treatments for Raynaud’s?
stopping smoking (increased risk in smokers) avoiding cold vasoactive therapies
What are the two types of Raynaud’s?
Primary - idiopathic (unknown cause, maybe hereditary)
Secondary - associated with connective tissue disorders, obstruction (atherosclerosis) and some drug side effects (beta-blockers and chemotherapy)
Name 4 endothelial mediators that regulate VSMC contractility
What does each mediator lead to?
nitric oxide - vasorelaxation
prostanoid - vasorelaxation and contraction
endothelin - vasocontraction
angiotensin II - vasocontraction
How is the NO pathway targeted?
NO donors can be converted into NO by mitochondrial aldehyde dehydrogenase
Give examples of NO donors and when they are used
nitroglycerine - angina and IHD
sodium nitroprusside - emergency hypertension
inhaled NO - severe pulmonary hypertension
What treatments are given to potentiate vasorelaxation via the prostanoid pathway?
What do these treatments do?
When are they used?
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
What treatments are given to potentiate vasorelaxation via the endothelin pathway?
What do these treatments do?
When are they used?
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)
What treatments are given to potentiate vasorelaxation via the angiotensin pathway?
When are they used?
ACE inhibitors - captopril and enalapril - hypertension, heart failure, post-MI
AT1 receptor antagonists - sartans - reduce blood pressure
Give an example of an ACE inhibitors
What does this treatments do?
What are the side effects?
captopril
blocks the ACE enzyme site
hypotension, cough, proteinuria, changes to taste
Give examples of Sartans
What does this treatment do?
Losartan and Valsartan
antagonise the AT-1 receptor and inhibit production of angiotensins in the renin-angiotensin-aldosterone system
Describe the angiotensins
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
What was the problem with sympathetic NS acting drugs?
too many (multiple) or severe side effects
Give examples of VSMC directly acting therapies
What do they treat?
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
What can’t be used in combination with PDE inhibitors? Why?
NO donors (nitroglycerin) and angina therapies combination causes severe drop in blood pressure
How do PDE inhibitors work?
hydrolyse cAMP and cGMP leading to activation of PKA and PKG (respectively) leading to potentiation of myosin phosphatase and muscle relaxation
