L14: Cardiovascular Pharmacology - Blood Pressure Control

Question 1

What is the structure of an arteriole?

Answer 1

Endothelium, smooth muscle fiber

Question 2

How is the blood pressure calculated?

Answer 2

BP = CO x PVR
CO - cardiac output (pre-load)
PVR - peripheral (systemic) vascular resistance (after-load)

Question 3

What is afterload? How is it determined?

Answer 3

The afterload is the amount of pressure that the heart needs to exert to eject the blood during ventricular contraction (the force against which the heart has to pump). It’s recorded as systolic pressure of the heart.
Determined by tone (dilation and constriction) in resistance arterioles.
i.e. smaller diameter of arteriole, heart works harder, PVR increases, afterload increases

Question 4

Which is the key site for blood pressure regulation?

Answer 4

Arterioles, changes in constriction or dilation can have a big effect on BP.

Question 5

What are the key systems for BP regulation?

Answer 5

Autonomic nervous system:
- mainly sympathetic (noradrenaline, alpha1 adrenoreceptor)

Circulating hormones:
- adrenaline (adrenal gland, alpha1 adrenoreceptor)
- angiotensin II (renin-angiotensin-aldosterone system; eminates from kidney)
- vasopressin (from posterior pituitary in response to reduced fluid load)
blood vessel constriction (increase [Ca2+])

Local control:
- endothelium-derived factors (endothelin, nitric oxide (NO), prostacyclin (PGI2))
constriction and relaxation of blood vessels

Question 6

What regulates vascular tone locally?

Answer 6

• Nitric oxide (NO) and prostacyclin (PGI2) cause relaxation
• Endothelin-1 (ET-1) and angiotensin II (Ang II) cause constriction

Question 7

Where is NO produced and how does it cause relaxation in vascular tone? What would need to be adjusted in NO sytnhesis to change the BP?

Answer 7

• In endothelium L-Arginine is converted to NO
• taken up by smooth muscle cells, NO acts on guanylate cyclase which converts GTP to cGMP
• this inhibits intake of calcium, which causes relaxation

If NO conversion is inhibited, it increases the blood pressure

Question 8

What disease is angina? What causes it?

Answer 8

Angina is where you have attacks of chest pain caused by reduced blood flow to your heart. Angina is usually caused by the arteries supplying blood to the heart muscles becoming narrowed by a build-up of fatty substances.

Question 9

How can angina be treated?

Answer 9

By administration of nitrates, which mimic NO and act on guanylate cyclase. Inhibits Ca2+ intake and relaxes the muscle. After-load decreases, as less energy is needed for the heart to pump.

Question 10

What does cGMP phosphodiesterase (PDE) do? Which drugs target it?

Answer 10

Breaks down cGMP, increases calcium uptake, promotes constriction. Example: viagra

Question 11

What structure sets the heart rate?

Answer 11

Sino-atrial node set the heart rate, specialized cells, spontaneously contracting myocytes

Question 12

Which systems and their receptors regulate the heart rate?

Answer 12

Sympathetic NS increases the heart rate, acting on beta-1 adrenoreceptors
Parasympathetic NS decreases the heart rate, acting on M2 receptors.

Question 13

What determines stroke volume?

Answer 13

Venous return (amount of blood entering ventricle during diastole); determined by pre-load and contractility

Question 14

What increases strokes volume? What’s the outcome of it?

Answer 14

Increases preload -> increase stroke volume -> increase cardiac output
The more blood goes into the heart, the more force heart can generate

Question 15

What is preload?

Answer 15

The preload refers to the amount of blood already in your ventricles when you’re ready to pump it out

Question 16

What determines venous return / preload?

Answer 16

Venous tone (capacitance) and blood volume (Na+ and water excretion)
When capacitance is high, veins are dilated. More blood in veins, less blood in the heart and vice versa.

Question 17

What’s the effect on capacitance when increasing venous tone?

Answer 17

Increasing venous tone results in lower capacitance, veins constricted.

Question 18

What’s the effect on Na+ and water excretion when increasing blood volume?

Answer 18

Increasing blood volume results in lower Na+ and water excretion

Question 19

What determines contractility?

Answer 19

• Sympathetic nervous system
• circulating hormones
• Frank-Starling mechanism

Question 20

What is contractility?

Answer 20

Contractility can be defined as any increase in the force of contraction (Work) that CANNOT be attributed to the Frank–Starling mechanism of the heart

Question 21

How do kidneys detect pressure changes?

Answer 21

Pressure detected in specialised juxtaglomerular cells close to the afferent arteriole.

Question 22

What’s the effect of low pressure detected in juxtaglomerular cells?

Answer 22

When low pressure is detected in juxtaglomerular cells, renin is secreted

Question 23

What’s the effect of renin secretion?

Answer 23

• Renin converts angiotensinogen to Angiotensin I.
• Angiotensin I is then converted to Angiotensin II.
• Angiotensin II acts on arterioles, results in increase in peripheral vascular resistance (PVR) (increase in constriction) and in increase in after-load.
• Angiotensin II also acts on adrenal cortex, stimulates aldosterone secretion, which results in Na+ and water retention, thus increase in blood volume and pre-load.
  Together they increase heart rate.

Question 24

Explain the mechanism of Renin Angiotensin Aldosterone System (RAAS)

Answer 24

Renin converts angiotensinogen to angiotensin I, which is the converted to angiotensin II by angiotensin-converting enzyme. Angiotensin II then acts either on arterioles or adrenal cortex.

Question 25

In what ways does sympathetic nervous system affect blood pressure? What are the receptors in place?

Answer 25

• Sympathetic nerves (beta-1 adrenoreceptor) increase HR, conduction and contractility.
• Sympathetic (alpha-1 adrenoreceptor) increases after-load in arterioles and pre-load in veins. Increase in HR.
• Sympathetic activation (beta-1 adrenoreceptor) leads to renin release and activation of RAAS

Question 26

What is baroreceptor reflex?

Answer 26

Your baroreceptor reflex keeps your blood pressure steady when you experience something that raises or lowers it. A complex series of actions quickly bring your blood pressure back into a normal range

Question 27

Where are baroreceptors located?

Answer 27

in carotid sinus and aortic arch

Question 28

What is the purpose of baroreceptors?

Answer 28

• Detect change in bp e.g. standing up
• and adjust autonomic output to heart and blood vessels to correct bp (postural hypotension)

Question 29

What is postural hypotension?

Answer 29

Postural hypotension (also called orthostatic hypotension) is a drop in blood pressure when you stand up after lying or sitting down

Question 30

Define hypertension

Answer 30

Pressure in the vessels is too high (140/90mmHg, normal 120/80mmHg)

Question 31

What is systole?

Answer 31

Contraction of the heart

Question 32

What is diastole?

Answer 32

Dilation

Question 33

Why is hypertension dangerous?

Answer 33

No symptoms, increases risk of coronary heart disease, heart attack, stroke, kidney damage and heart failure (damages vessels)

Question 34

What is primary hypertension? What is the cause?

Answer 34

No identifiable cause e.g. could be genetic or environmental, most common

Question 35

What is secondary hypertension? What is the cause?

Answer 35

5% of cases the cause can be identified. Could be:
- adrenal disease (catecholamine secreting tumour or excessive steroids)
- kidney disease (increased salt or water retention)
- doctors (corticosteroids, sympathomimetics)

Question 36

What are the non-pharmacological approaches to reduce hypertension?

Answer 36

weight loss, increase exercise, reduce dietary salt, alcohol reduction

Question 37

What are diuretics? How do they act?

Answer 37

Drugs increasing Na+ and water loss, therefore reduce blood volume and pre-load. Some also have direct effects on arteriolar tone, so also reduce after-load.

Question 38

What are the two kinds of diuretics? What are their functions?

Answer 38

Loop diuretics - impair Na+ readsorption in ascending loop of Henle
Thiazide diuretics - inhibit Na+ readsorption in distal tubule; also dilate arterioles; cause K+ loss, this must be supplemented
Essentially both increase water loss

Question 39

How do beta-adrenoreceptor antagonists affect BP?

Answer 39

• reduce cardiac output
• reduce renin release from kidney, decrease RASS activation, therefore decrease pre-load and after-load
• action in CNS to reduce bp
• few side effects e.g. postural hypotension, but not used in asthmatics

Question 40

How do calcium-channel blockers affect BP?

Answer 40

• Block L-type voltage-gated Ca2+ channels, Ca2+ entry
• therefore, reduce muscle contraction

Question 41

What are the types of calcium channel blockers?

Answer 41

• Dihydropyridines are relatively selective for vascular smooth muscle
• Phenylethylalkamines less selective, have more effects in the heart, may cause heart block

Question 42

How do drugs targeting RAAS work?

Answer 42

• Many of the drugs target anigiotensin-converting enzyme (ACE) and inhibit it (ACE inhibitors), decrease pre-load and after-load.
• AT1 receptor antagonists block AT1 receptors, decrease pre-load and after-load.
• renin inhibitors target renin, no conversion of angiotensinogen to angiotensin I, decrease pre-load and after-load.
• mineralcorticoid receptor antagonist

Question 43

What are sympatholytic drugs? How do they act?

Answer 43

Drugs that inhibit release of NA or block its effects at receptors (not used as much anymore). i.e. ganglion blockers, methyldopa, adrenergic neuron blockers.
some alpha-1 adrenoreceptor antagonists used to reduce afterload, but can cause postural hypotension