Drugs and the Vasculature

Question 1

What are some VSM mediators that can increase [Ca2+] and stimulate a VSM contraction?

Answer 1

AngII -> AT1r
PGG2, PGH2 -> TP (T-prostanoid receptor)
ET1 -> ETA/B

Question 2

What are some endothelial cell agonists that can stimulate a relaxation from an increase in [Ca2+] ?

Answer 2

NO
CNP – C-Type Naturietic Peptide
PGI2
EDHF – Endothelial Hypopolarising Factor

Question 3

What is the role of arterioles in hypertension?

Answer 3

Arterioles contribute the greatest to blood pressure regulation

These vessels exhibit “vascular tone” and so always display a partial state of constriction

Hypertensive patients tend to have a raised base vascular tone -> more TPR -> more BP

Question 4

What are the steps in hypertension treatment?

Answer 4

Step 1 – Single Therapy:

• Under 55 – ACEi or ARB (Angiotensin Receptor Blocker)
• Over 55, Afro-Caribbean – CCB or Thiazide diuretic

Step 2 – Dual Therapy:

• ACEi and CCB
• ACEi and thiazide diuretic

Step 3 – Triple Therapy:
- ACEi, CCB and thiazide diuretic

Step 4 – Symptomatic Relief:

• Low-dose spironolactone (diuretic therapy)
• b-blockade or a-blockade

Question 5

What stimulates the RAS?

Answer 5

LOW renal Na+ reabsorption
LOW renal perfusion pressure
HIGH SNS activation

Question 6

What do ACE inhibitors do?

When are they used?

Answer 6

ACEi decrease AngII production and increase Bradykinin

Uses:

• Hypertension
• Heart failure
• Post MI
• Diabetic nephropathy.
• Progressive renal insufficiency
• High CVS-disease-risk patients

e.g enalapril

Question 7

What does angiotensin II do?

Answer 7

SNS activation/ thirst
vasoconstriction
aldesterone
salt and water retention

Question 8

Why can you use ACE inhibitors in hypertension and heart failure?

Answer 8

Hypertension:

• Reduce TPR – more bradykinin & less AngII -> reduces TPR via less AT1R-mediated vasoconstriction so less BP and more bradykinin vasodilation
• Sodium retention – less Na+ retention in the kidneys via blocked actions of AngII on the AT1R in the kidneys AND less aldosterone secretion as blocked AT1R in the adrenal medulla - decreased venous return -> decreased CO

Heart Failure:

• Reduce TPR – less vasoconstriction via AT1R in the peripheral vasculature so less TPR so less afterload on the heart so ionotropic effects of the heart decrease
• Reduce preload – venodilation (bradykinin?) means less preload

Question 9

What do angiotensin receptor blockers do?

Answer 9

e.g. Losartan.

Prevent binding of AngII to AT1 receptors

Uses – hypertension and HF

Question 10

What are side effects of ACEi and ARBs?

Answer 10

• Cough – ACEi (prevents bradykinin beakdown -> cough)
• Urticaria/angioedema – ACEi rarely
• Hypotension – ACEi, ARBs
• Hyperkalaemia – ACEi, ARBs – care with K+ supplements or K+-sparing diuretics (aldosterone promotes inseertion of sodium channels and sodium potasium ATPase into tubules - ACE-> less aldesterone -> less channels inserted -> les k+ lost in urin -> build up of K+in blood)
• Foetal injury – ACEi, ARBs
• Renal failure (in patients with renal artery stenosis) – ACEi, ARBs
• Glomerular filtration is maintained by AngII so you need to be careful in renal failure patients

Question 11

What does calcium do in the cell?

Answer 11

Smooth muscle contraction:

• Membrane depolarisation opens VGCC
• Ca2+ enters and binds calmodulin (CaM)
• Ca2+-CaM complex activates MLCK
• MLCK mediated phosphorylation -> VSM contraction

Question 12

How can CCBs treat hypertension?

Answer 12

Dihydropyridines (DHPs) – non-rate limiting:

• Amlodipine – no negative ionotropic effect
• Prophylactic treatment of angina

Non-DHPs – rate-limiting:
- Verapamil – negative ionotropic effect

Amlodipine is used to treat hypertension as it does not have an ionotropic effect on the heart

• DHPs inhibit Ca2+ entry into the VSMCs so less contraction of the cells -> less TPR -> less BP

** powerful vasodilation can lead to a reflex tachycardia and increased ionotropy thus increased myocardial oxygen demand.

Question 13

Why do we use different drugs for different groups of people i stage 1 therapy?

Answer 13

Under 55 – ACE or ARB (Angiotensin Receptor Blocker)

• The reason those drugs are the first line drugs is due to the good patient adherence as seen in studies
• Higher adherence = less side effects
• Not much difference between ACEi and ARB in reducing BP

Over 55, Afro-Caribbean – CCB or Thiazide diuretic
- This group of people have a different drug schedule due to low plasma renin activity and so ACEi doesn’t work as well – the studies into this are not confirmed

Question 14

How do a-blockers treat hypertension?

Answer 14

e.g. Prazosin, Phentolamine

a-blockers block a1-mediated vasoconstriction

Prazosin is an a1-antagonist

Phentolamine is an a1/a2 antagonist.

Action against a2 blocks the –ve feedback of NA release and so there is an enhanced NA release and SNS response

This can lead to increased HR (not reflex)