L8 - Physiology of the Vasculature II Flashcards
What 5 diseases are there where we target the vasculature to treat them?
Hypertension Heart Failure Angina Pulmonary Hypertension Raynaud syndrome
How does smoking damage vascular function?
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
How does diabetes damage vascular function?
Impairs eNOS –> less NO production
Increased inflammation - ↑ endothelin/cytokine production
Net result - vasoconstriction
How does obesity damage vascular function?
Fatty plaque –> physical separation between endothelial cells and VSMCs
NO cannot reach smooth muscle –> no arterial relaxation
How does ageing damage vascular function?
Increased BP Impaired arterial relaxation - Fibrosis - Calcification - stiffens arteries - VSMCs become senesce - can undergo apoptosis - Elastin fragmentation
How does infection damage vascular function?
Immune response –> activates endothelium –> recruitment of leukocytes to artery wall
Weakens atherosclerotic plaque - ↑ vulnerable to rupture
These stimuli generally activate pathways –> VSCM contraction
Does smoking, diabetes, obesity and ageing cause vasculature to be more contracted or relaxed?
Contracted –> hypertension
Hypertension overview
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
Symptoms of hypertension
Breathlessness
Fatigue
Fluid retention
Overall cardiac output is not adequate to meet metabolic demands
Heart failure overview
Inadequate cardiac output to meet metabolic demand
Disease of heart itself
Causes of heart failure
Secondary to Coronary Artery Disease and/or myocardial infarction
Viral infections causing inflammation of the heart tissue
Kidney failure
Sleep apnea
Angina overview
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
Causes of angina
Due to coronary artery disease/atherosclerosis
Pulmonary hypertension overview
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
What is Raynauds disease?
Over-activation of sympathetic nervous system –> inappropriate vasoconstriction of smaller arteries/arterioles
Symptoms of Raynauds disease
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
Treatments for Raynauds disease
Stop smoking
Avoid cold
Vasoactive therapies
Primary Raynauds
If idiopathic
May be somewhat hereditary
Increased risk in smokers
What is secondary Reynauds associated with?
Connective tissue disorders
Obstruction (atherosclerosis)
Some drug side effects (beta blockers, chemotherapy)
How do healthy endothelial cells relax?
Activated by high shear blood flow
Get activation of eNOS
Mediators (Ach, 5-HT) activate GPCRs –> IP3 –> increase Ca –> increased activation of eNOS –> relaxation
How do activated endothelial cells contract?
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
What are the two places Ca is stored and released from during VSMC contraction?
Plasma membrane
Sarcoplasmic reticulum
How do second messengers lead to the release of SR Ca during VSMC contraction?
Second messengers released through activating G proteins –> IP3 –> release of Ca for SR
What are the 3 mediators regulating VSMC relaxation?
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
How does NO play a role in VSMC relaxation?
NO released from endothelial cells
Activates guanylyl cyclase –> cGMP
Activates PKG –> activates myosin phosphatase –> more inactive myosin
How do Gs couples receptors play a role in VSMC relaxation?
Activate adenylyl cyclase –> cAMP
How do PDE enzymes oppose VSMC relaxation?
Break down cGMP and cAMP
What are the 3 examples of NO donors used as treatment?
Nitroglycerine
Sodium Nitroprusside
Inhaled NO
What does nitroglycerine treat?
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
What does sodium nitroprusside treat?
Emergency hypertension
What does inhaled NO treat?
Pulmonary hypertension (severe)
What are the 3 examples of prostanoids used as treatment?
Iloprost
Epoprostenol
Corticosteroids
What does iloprost treat?
Prostacyclin stable analogue
Pulmonary hypertension
Raynaud syndrome
What does epoprostenol treat?
IP receptor agonist
Some uses in Pulmonary Hypertension
What do corticosteroids treat?
Suppress formation of prostaglandins
Prevents shock (hypotension)
Long term use not recommended – can suppress immune system broadly
What are the 2 examples of endothelin inhibition used as treatment?
Phosphoramidon
Bosentan
What does phosphoramidon treat?
Endothelin Converting Enzyme inhibitor
Experimental tool
What does bosentan treat?
Pulmonary Hypertension
Blocks both endothelin A and B receptors
What are the two approaches to target angiotensin II to get a relaxation response?
Target
- Production of angiotensin II
- Activation of angiotensin II at AT1 receptor
What are the 5 examples of targeting angiotensin II used as treatment?
AT1 receptor antagonists - Sartans – Losartan and Valsartan ACE inhibitors - Captopril - Enalapril and lisinopril
What does losartan and valsartan treat?
Blood pressure reduction
Also inhibit production of angiotensin at Renin-Angiotensin-Aldosterone system
- Angiotensin I produced in the kidney
What does captopril treat?
Hypertension, heart failure, after myocardial infarction
Blocks active site of enzyme
What are the side effects of captopril?
Hypotension
Cough
Proteinuria
Taste
What does enalapril and lisinopril treat?
Hypertension, heart failure, after myocardial infarction
Require conversion to active metabolite
Longer acting
What are the 3 types of directly acting therapies?
Ca channel blockers
KATP channels activators
PDE inhibitors
What are two examples of Ca channel blockers?
Nifedipine
Verapamil
What are 3 examples of KATP channel activators?
Minoxidil
Diazoxide
Nicorandil (NO donor)
What are 2 examples of PDE inhibitors?
Sildenafil = Viagra
Tadalafil
What do minoxidil and diazoxide treat?
Severe hypertension
What does nicorandil treat?
Refractory angina
Which treatment type should not be taken in combination with NO donors?
PDE inhibitors
As they can cause a severe drop in blood pressure
Why are many sympathetic nervous system-acting drugs effective in hypertension now rarely used?
Multiple or severe side-effects
What are the 5 drugs used to treat hypertension?
Sodium nitroprusside ACE inhibitors Sartans Nifedipine, verapamil Minoxidil, diazoxide
What are the 2 drugs used to treat heart failure?
ACE inhibitors
Verapamil
What are the 3 drugs used to treat angina?
Nitroglycerine
Diltiazem
Nicrorandil
What are the 4 drugs used to treat pulmonary hypertension?
Inhaled nitric oxide
Iloprost
Bosentan
Sildenafil and Tadalafil
What are the 3 drugs used to treat Raynauds syndrome?
Iloprost
Nifedipine
Sildenafil
