Lecture 8 Physiology of the Vasculature II Flashcards
How does atherosclerosis impact the ability of the endothelium to regulate vascular smooth muscle
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
What can happen specifically to the endothelium as a result of a loss of the glycocalyx as a result of oxLDL
They can become hyper-responsive and more likely to release contractile mediators
What happens as a result of calcification of the blood vessels in disease
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
Loss of which extracellular matrix protein in the vessel wall can also play a role in disease
Elastin
Hypoxia uncouples eNOS T or F
T
What is the evidence for the incidence of hypertension
Around 30% of people are affected in England
What risk is massively increased in patients left untreated for hypertension
Increased risk of heart attack and stroke
What is the leading risk factor for the overall global burden of disease
Hypertension
What are the symptoms of hypertension
Breathlessness fatigue fluid retention as cardiac output not adequate to meet metabolic demands
What is the most common cause of hypertension
Secondary to atherosclerosis
Heart Failure is where there is an inadequate cardiac output to meet metabolic demand what is the most common cause of heart failure
Disease of heart itself secondary to coronary artery disease (atherosclerosis) and/or myocardial infarction
Other than MI and atherosclerosis what else can cause heart failure
Severe viral infections kidney failure and sleep apnoea
What is meant by angina
Angina is where the oxygen supply to the heart is insufficient upon exertion leading to chest pain
What is the main cause of angina
Coronary artery disease
What are the two types of angina and how do they differ
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
What is pulmonary hypertension
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
What are the effects of pulmonary hypertension
Increased pressure in the lungs and in the right side of the heart. This often results in right sided heart failure
What is the prognosis for patients with pulmonary hypertension
There is an extremely poor prognosis with patients usually surviving only 1-3 after diagnosis
What is Raynaud’s disease
This is where there is an inappropriate vasoconstriction of smaller arteries/arterioles. This is most commonly seen in the hand and fingers
How does Raynaud’s disease usually present
White then blue fingers when exposed to the cold. Then redness upon warming up (reactive hyperaemia return of blood flow)
What happens in severe cases of Raynaud’s disease
It can cause ulceration and gangrene
What are the risk factors for Raynaud’s disease
Smoking hereditary component connective tissue disorders
What causes Raynaud’s disease
The spasms in the VSMCs of the arteries are due to an overactivation of the sympathetic nervous system
Other than avoiding cold and smoking cessation what therapies are often administered to patients with Raynaud’s
Vasoactive therapies that promote vasodilation
What are the 4 pathways by which the endothelium regulate the VSMCs and what is the effect of each
NO – relaxation angiotensin II – constriction prostanoids – constriction and relaxation endothelin – constriction
What are the three drugs used to target the NO pathway and trigger vasodilation
Glyceryl trinitrate nitroprusside and inhaled NO
Which NO donor is commonly used in angina and how does it act
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
Which NO donor therapy is often used in severe hypertension and hospital settings where is can be delivered intravenously
Nitroprusside
Which NO therapy isn’t an NO donor and is used mainly in pulmonary hypertension and in the clinical setting
Inhaled NO
What is the aim of prostanoid therapy with regard to the individual prostanoids involved
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
What is the mechanism of action of Iloprost
Iloprost is a stable analogue of prostaglandin I2 that binds to the IP-R and increases cAMP
What is the main indication for iloprost
Pulmonary hypertension and Raynaud’s disease
What is the mechanism of action of Epoprostenol
Epoprostenol is an IP-R agonist that binds to the IP-R and increases cAMP
What is the main indication for epoprostenol
Pulmonary hypertension
What is the effect of corticosteroids on the prsotenoid pathway
Corticosteroids decrease COX2 transcription and hence suppresses the formation of prostaglandins. These are used to cause a vasoconstriction
Why do we want to target drugs just for the ETA receptor in terms of vascular therapies
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
Give an example of a vasoactive drug that targets the endothelin pathway
Bosentan is a drug that non-specifically blocks ETA and ETB receptors and causes vasodilation. It is used in the treatment of pulmonary hypertension
When are ACE inhibitors often used in vascular disease
In hypertension and heart failure where this has occurred after myocardial infarction
What is the mechanism of action of captopril
Captopril blocks the active site of the ACE enzyme
What are the side effects of ACE inhibitors
Hypotension drug cough proteinuria and a change in taste perception
What is the benefit of enalapril and lisinopril over captopril
These drugs require conversion to an active metabolite. They therefore are much longer acting drugs
Give some examples of AT-1 receptor antagonists used in hypertension
Losartan valsartan
Which enzyme cleaves angiotensinogen to angiotensin I
Renin released by the JGA of the kidney
Which enzymes converts angiotensin I to angiotensin II
ACE
Where is ACE specifically expressed
In the renal and lung endothelium
Where is angiotensinogen produced
In the liver
As well as targeting the endotheliums’ regulation of VSMCs what other target are there for therapies in vascular disease
Targets of the smooth muscle itself
What are the opposing effects of adrenoceptor agonists in the vascular system
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
Many sympathetic nervous system-acting drugs effective in hypertension now rarely used due to multiple or severe side-effects T or F
T
Which Ca2+ channel blockers are used in hypertension
Nifedipine verapamil and diltiazem
Which Ca2+ channel blockers are used in angina
Nifedipine and diltiazem
Which Ca2+ channel blocker is used in Raynaud’s
Nifedipine
Give some examples of K+ channel activators used in hypertension
Minoxidil diazoxide and nicorandil
What is the additional benefit of nicorandil that makes it useful in the treatment of angina
As well as it opening K+ channels nicorandil is an NO donor and is therefore quite often used in refractory angina
How can PDE be targeted in the treatment of pulmonary hypertension
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)
What is the major contraindication of PDE inhibitors
They should never be used in conjunction with an angina treatment such as NO donors. This could dangerously reduce blood pressure in the patients
