Cardiovascular: Hypertension

Question 1

Describe the structure of resistance arteries?

Answer 1

1. Endothelium releases vasodilators such as NO (nitro oxide) and PGI2 (Prostacyclin)
2. Innervated by sympathetic nerves that surround the resistance arteries
3. Noradrenaline acts on the a1 receptor on the arteries which causes the vsm to contract

Question 2

Explain how a smooth muscle cell contracts?

Answer 2

1. Thick filaments contain myosin and thin actin
2. Dense bodies are Cytoplasmic anchorage points
3. During contraction thick and thin filaments contract
4. Process involves actin and myosin cross bridge cycling (involves calcium)
5. Shortens muscle fibre, shortens and “balloons”

Question 3

Explain how the contraction of vascular smooth muscle occurs?

Answer 3

1. G protein coupled Q receptor on the surface
2. Phospholipase C produces two signalling molecules called DAG and IP3
3. IP3 is a signalling molecule that affects the sarcoplasmic reticulum
4. IP3 binds to the sarcoplasmic reticulum to release calcium
5. Sarcoplasmic reticulum (same as Endoplasmic) contains a lot of calcium
6. Calcium is positively charged which is released into the cytosol via a voltage gated calcium channel
7. The calcium activates the Calmodulin which activates the myosin light chain kinase (MLCK) which is part of the thick filaments of smooth muscle
8. Phosphorylation of MLCK causes the real contraction

Question 4

What is the endothelium responsible for?

Answer 4

1. Causing the contraction and relaxation of the smooth muscle cells in the artery
2. A rise in calcium causes an increase in contraction
3. NO, EDHF and PG12 roles are to remove the calcium to cause the smooth muscle to relax

Question 5

Explain the process of the endothelium dependent relaxation (aorta practical)?

Answer 5

1. Increase in extra cellular calcium activates NO synthase, COX and EDHF
2. NO diffuses to small muscle cell
3. Activates soluble guanylate cyclase (SGC) which generates cGMP
4. cGMP evokes relaxation by protein kinase G
5. Protein kinase G prevents Ca2+ release, Ca2+ entry and regulates the myosin light chain kinase
6. COX derived PGI2 diffuses to smooth muscle cell to activate the IP receptor
7. IP receptor couples ot AC- cAMP generated activates pKa
8. pKa regulates MLCK and activates some smooth muscle K+ channels

Question 6

What is the purpose of each vasodilator drug and give examples of them?

Answer 6

1. Relax smooth muscle with varying mechanisms
2. Nitrates: produce NO
3. Potassium channel activators: Hyper polarise smooth muscle to prevent the entry via voltage gated calcium channels (VGCC)
4. Calcium channel blockers block VGCC
5. Some prevent the action of vasoconstrictors such as angiotensin or noradrenaline

Question 7

Describe how the calcium channel blocker works in hypertension?

Answer 7

1. Block smooth muscle cell and voltage gated calcium channels
2. First tier therapeutic agent in elderly and african/Caribbean populations
3. Second line for people under 55
4. Not used in pregnancy

Question 8

What are the main drugs that block L type voltage gated calcium channels and what are they associated with?

Answer 8

1. Vascular: (most effective): dihydropyridines such as Amlodipine
2. Cardiac: Phenethylalkylamine: Verapamil
3. Mixed: Benzothiazepines: Diltiazem

Question 9

What are the side effects of calcium channel blockers?

Answer 9

1. Postural hypotension
2. Flushes
3. Tremor
4. Cardiac effects (mainly phenethylalkylamines and benzothiazepine)
5. AV block
6. Negative inotropic effect leads to weakened heart beat
7. Nifedipine increases mortality following MI

Question 10

Describe how the potassium channel blocker works?

Answer 10

1. Decreases the positive charge in the cytoplasm that’s caused by the increase in calcium
2. Acts as a break to cause hypopolarisation (increase in negative charge)
3. Reduces the stimulus for the calcium channel which leads to calcium binding to calmodulin: leading to no constriction

Question 11

Give an example of potassium channel activators used, what it’s used for and the side effects?

Answer 11

1. Minoxidil
2. Severe hypertension or if patient has renal failure
3. Hypertension resistance to ACD strategy then use with diuretic, beta blocker or both
4. Side effects:
   - Reflex tachycardia (increased HR)
   - Fluid retention
   - Facial hair growth

Question 12

Give the name of the direct acting vasodilator used and describe its clinical use and side effects?

Answer 12

1. Hydralazine- Hypertension resistant to ACD
2. Clinical usage:
   - Pregnancy
   - Hypertensive emergency
   - Combination with beta blockers and thiazide diuretics
3. Side effects:
   - Reflex tachycardia
   - Fluid retention
   - Lupus like syndrome

Question 13

Describe the Dopamine D1 agonist drug, it’s clinical use and side effects?

Answer 13

1. Fenoldopam
2. More effective in renal and coronary arteries where D1 expression is high
3. Increase renal perfusion and naturesis (Na excretion- highly expressed in kidneys)
4. Short acting
5. Clinical use
   - Hospital severe hypertension
   - Kidney transplant surgery (blood flow to kidneys directly)
6. Side effects
   - Reflex tachycardia, not normally a problem due to short term use

Question 14

Describe how alpha adrenoceptor antagonists work?

Answer 14

They block the alpha 1- adrenoceptor which means that noradrenaline cannot active the adrenoceptor

Question 15

Give examples of alpha adrenoceptor antagonist drugs and describe how they work?

Answer 15

1. Doxasozin, prazosin
2. Block the action of sympathetic nervous system (noradrenaline) on “resistance” arteries: used when other drugs have failed
3. Relax electrical storage vessels in venous system
4. This lowers the cardiac output, venous return and preload on the heart
5. Reduced stroke volume
6. Less tachycardia than other drugs, postural hypotension, fatigue, dizziness