03-09-22 - Pathophysiology of Hypertension

Question 1

Learning outcomes

Answer 1

• Define primary and secondary hypertension and recognise their grades and features.
• Relate the proposed causes and risk factors to the pathogenesis of primary hypertension.
• Identify causes of secondary hypertension across different organ systems and clinical conditions.
• Describe the major consequences of uncorrected, chronically elevated hypertension.

Question 2

What is pulmonary hypertension (PH)?

What are 6 of its cause?

What 6 things can pulmonary hypertension be due to?

What does it cause the heart to do?

When it is more common?

When is it usually diagnosed?

Answer 2

• Pulmonary hypertension (PH) is the Increased blood pressure in the arteries of the lungs
• The cause of hypertension is often not known
• Pulmonary hypertension can be due to:
  1) Hypoxia
  2) Endothelial dysfunction
  3) Genetics
  4) Blockage/damage to blood vessel
  5) Side effect of drugs
  6) Left-sided heart failure
• Pulmonary hypertension causes the right side of the heart to work harder
• PH is More common in patients with another heart or lung condition
• It is usually only diagnosed when severe and symptomatic

Question 3

What is Systemic arterial hypertension (SAH)?

What values are typically considered SAH?

What 4 things is SAH major risk factor for?

What things are risk factors for developing SAH?

Answer 3

• Systemic arterial hypertension (SAH) is the condition of persistent non-physiologic elevation of systemic blood pressure
• Typically values for SAH are:
• Systolic > 140 mmHg and/or
• Diastolic > 90mmHg
• SAH is a major risk factor for:
  1) CV disease and heart attack
  2) Stroke/dementia
  3) Kidney failure
  4) Vision loss
• Risk factors for developing SAH:

1) Age

2) Weight

3) Sex
* < 60 years more prevalent in males
* > 60 years more prevalent in females

4) Race
* African Americans disproportionally affected

5) Education status

6) Diet

Question 4

When should adults have blood pressure measured?

How many readings are required to get an average?

Once blood pressure is measured, what 2 ways can be confirmed it?

Answer 4

• Adults should have blood pressure measured:
  1) All adults > 40 should have BP measured
  2) < 40 years old with family history of atherosclerosis
• To get an average, there should be a minimum of 3-4 pairs of readings gathered over 3-4 months (unless there is severe hypertension)
• Ways to confirm blood pressure after measuring it:

1) Ambulatory blood pressure monitoring (ABPM)
* Measured twice per hour during waking hours
* At least 14 measurements to calculate average

2) Home blood pressure monitoring (HBPM)
* Monitored twice daily (day/night, sitting)
* 2 recordings, 1min apart for 7 days (at least 4)
* All recordings after 1st to calculate average

Question 5

What clinic blood pressure measurements and subsequent confirmation blood pressure measurements qualify for:
* Low BP
* Normal BP
* Stage 1 hypertension
* Stage 2 hypertension
* Severe hypertension

Answer 5

• Clinic blood pressure measurements and subsequent confirmation blood pressure measurements for:

1) Low BP
* Systolic of 40 – 90 mmHg
* Diastolic of 40 – 60mmHg

2) Normal BP
* Systolic of 90 - 120 mmHg
* Diastolic of 60 – 80 mmHg

3) Stage 1 hypertension
* Clinic BP is 140/90 mmHg or higher
* Subsequent ambulatory or home blood pressure monitoring (ABPM or HBPM) daytime average is 135/85 mmHg or higher

4) Stage 2 Hypertension
* Clinic BP is 160/100 mmHg or higher
* Subsequent ABPM or HBPM daytime average is 150/95 mmHg or higher

5) Severe hypertension
* Clinic systolic BP is 180 mmHg or higher
* OR clinic diastolic BP is 110 mmHg or higher

Question 6

What is the diagnosis and treatment for clinic BP and ABMP and HPBM:
* Stage 1 hypertension
* Stage 2 hypertension
* Severe hypertension

Answer 6

What is the diagnosis and treatment for clinic BP and ABMP and HPBM:
* Stage 1 hypertension
* Stage 2 hypertension
* Severe hypertension

Question 7

What is primary hypertension?

What is it also known as?

How many cases of hypertension are primary hypertension?

What are risk factors of primary hypertension?

Answer 7

• Primary hypertension is that which has no apparent underlying cause
• Primary hypertension is also known as essential or idiopathic hypertension
• Approximately 90% of human hypertension cases are primary hypertension
• Risk factors of primary hypertension:
  1) Weight
  2) Lifestyle - Dietary sodium intake, lack of exercise, alcohol, smoking
  3) Genetic factors

Question 8

What is the formula for blood pressure?

What is the formula for cardiac output?

What regulates BP and local tissue flow?

Answer 8

• Blood pressure = Cardiac output x Total peripheral resistance (MABP = CO x TPR)
• Cardiac output (CO) = Stroke volume (SV) x Heart rate (CO – SV x HR)
• BP and local tissue flow is regulated by complex interactions of neurohormonal and local control systems
• Additional systems that regulate blood volume in relation also regulate blood pressure

Question 9

What are 3 possible contributors to hypertension?

Answer 9

• 3 possible contributors to hypertension:
  1) Increased sympathetic activity / sensitivity
  2) Renin-angiotensin-aldosterone system (RAAS)
  3) Circulating factors

Question 10

What are the Sympathetic and Parasympathetic nervous systems?

What 3 factors can the SNS control that affect blood pressure?

Answer 10

• The Sympathetic and Parasympathetic nervous system are two major efferent pathways controlling targets other than skeletal muscle
• 3 factors the SNS controls that affect blood pressure:

1) Blood vessel tone (responsible for vasoconstriction – increased blood pressure)

2) Heart rate and contractility (increases both – positive chronotropic and inotropic effects – increased blood pressure)

3) Adrenal gland secretion of adrenaline (increases stroke volume and heart rate, hence increasing cardiac output (CO = SV x HR)

Question 11

What are catecholamines?

What are 3 examples of catecholamines?

What do catecholamines do?

Describe 2 ways the sympathetic nervous system connects to effectors (4 steps each)

Answer 11

• Catecholamines are neurotransmitters in the central and peripheral nervous systems as well as hormones in the endocrine system
• Catecholamine examples:
  1) Noradrenaline (Norepinephrine)
  2) Adrenaline (epinephrine)
  3) Isoprenaline (synthetic β-agonist)
• Catecholamines bind adrenoceptors (adrenergic receptors) to elicit their actions
• How the sympathetic nervous system connects to effectors:
• Method 1:
  1) Short pre-ganglionic fibre releases acetylcholine (Ach) in sympathetic ganglion
  2) This Ach binds to nicotinic Ach receptors on the post-ganglionic neuron
  3) This long post-ganglionic neuron goes out towards effectors and releases the catecholamine Norepinephrine
  4) Norepinephrine binds to α and β adrenergic receptors on effectors, which can be smooth muscle, cardiac muscle, or glands
• Method 2:
  1) Short pre-ganglionic fibre releases acetylcholine (Ach) towards a chromaffin cell in the adrenal gland
  2) The Ach binds to nicotinic acetylcholine receptors in the chromaffin cell (adrenal glands acts as a ganglion for syanpse)
  3) This stimulates the release of adrenaline (epinephrine) into the vessels
  4) The adrenaline can travel to effectors, where it binds to α and β adrenergic receptors on effectors
   

Question 12

What are catecholamines?

What are 3 examples of catecholamines?

What do catecholamines do?

What are the 4 different types of adrenoreceptor?

How do catecholamine interaction with adrenergic receptors (adrenoreceptors) differ?

How is the intracellular action of a specific catecholamine determined?

Answer 12

• Catecholamines are neurotransmitters in the central and peripheral nervous systems as well as hormones in the endocrine system
• Catecholamine examples:
  1) Noradrenaline (Norepinephrine)
  2) Adrenaline (epinephrine)
  3) Isoprenaline (synthetic β-agonist)
• Catecholamines bind adrenoceptors to elicit their actions
• The 4 different types of adrenoreceptor are:
  1) α1
  2) α2
  3) β1
  4) β2
• Each catecholamine demonstrates different affinities to each receptor
• Intracellular action of a specific catecholamine is determined by the complement of receptors expressed on the cell surface (GPCR)

Question 13

Describe the effects of Adrenaline, Noradrenaline, and Isoprenaline on α1 and α2 receptor tissues.

What are these 2 receptor tissues?

Which catecholamine has the highest affinity for each receptor?

What effect does affinity have on the effect of the catecholamine on the effectors?

Answer 13

• Effects of Adrenaline, Noradrenaline, and Isoprenaline on α1 and α2 receptor tissues
• Which catecholamine has the highest affinity for each receptor
• The greater the affinity of a catecholamine for a receptor on an effector, the lesser the concentration of catecholamine required to achieve maximal effect on the effector

Question 14

Describe the effects of Adrenaline, Noradrenaline, and Isoprenaline on β1 and β2 receptor tissues.

What are these 3 receptor tissues?

Which catecholamine has a higher affinity for each receptor?

Answer 14

• The effects of Adrenaline, Noradrenaline, and Isoprenaline on β1 and β2 receptor tissues.
• Which catecholamine has the highest affinity for each receptor

Question 15

Describe the 4 pathways of sympathetic contribution to hypertension

Answer 15

• 4 pathways of sympathetic contribution to hypertension:

1) Increased signalling to vascular smooth muscle cells of blood vessels
* Norepinephrine acts on α1 receptors
* Increases vasoconstriction, which increases TPR, which increase BP

2) Increased signalling to pacemaker and contractile cells in heart
* Norepinephrine acts on β1 receptors
* Increases HR and contractility, which increases CO, which increases BP

3) Adrenal gland secretion of adrenaline
* Feeds into the first 2 pathways and has the same effects

4) Renin release
* Renin is released from juxtaglomerular cells of the kidneys in response to the circulating catecholamines that activate β1 adrenoreceptor on the kidneys
* This triggers RAAS pathway, which generates Angiotensin 2
* Angiotensin 2 acts as an AT1 and AT2 receptor agonist

• Roles of angiotensin 2:

1) Vasoconstriction
* Angiotensin causes vasoconstriction of renal arteries, which increases total peripheral resistance and constricts blood flow via the kidneys

2) Release of aldosterone
* Angiotensin 2 causes the release of aldosterone from the zona glomerulosa (outermost region) of the adrenal glands, which changes the volume of water excreted from the kidney by increasing Na+ and water reabsorption

3) Stimulation of release of ADH (anti-diuretic hormone / vasopressin) from the pituitary
* ADH increases blood volume by increasing water permeability in the renal collecting ducts, which decreases urine production

• All of these roles of angiotensin 2 lead to an increase in blood pressure

Question 16

What is the nephron?

What is the function of the nephron?

What is Na+ in the blood?

What is the role of Na+ in the kidney?

What must the kidneys balance in relation to water and Na+?

Why is this done?

What is this system a target for?

Answer 16

• The nephron is the functional unit of the kidney
• The nephron filters blood (180L/day) and produces urine
• Na+ is the predominant cation in the ECF (Blood compromises 36% of ECF volume – ECF is sum of plasma volume and interstitial fluid volume)
• Movements of Na+ established osmotic gradients for H2O movement - In the kidneys, wherever the sodium moves, the water will follow
• Na+ is freely filtered across the glomeruli of the nephron, with 99% being reabsorbed through the long tubule of the nephron back into the blood
• The kidneys must balance Na+ and water intake with Na+ and water excretion
• This is done to maintain blood volume that makes up ECF volume, and therefore long-term BP
• This system is a critical target for anti-hypertensives

Question 17

The RAAS system.

Describe the pathway in which decreased arterial pressure produces angiotensin 2

What vessels and receptors does angiotensin 2 act on?

What are 3 roles of angiotensin 2?

What do all of these roles lead to?

What is the purpose of the RAAS system?

Answer 17

• This full system is the RAAS system
• The pathway in which decreased arterial pressure produces angiotensin 2
  1) Decreased arterial blood pressure
  2) Leads to renin (enzyme) release from the juxtaglomerular cells of the kidneys
  3) Renin substrate angiotensinogen is released from the liver
  4) Venous blood from the liver and kidneys are mixes together
  5) Renin breaks down angiotensinogen into angiotensin 1
  6) This venous blood then circulates to the heart and then the lungs
  7) Converting enzyme in the lungs converts angiotensin 1 to angiotensin 2 (active for short period of time)
  8) Angiotensin rich blood then comes around the circulation
• Angiotensin acts on resistance vessels
• Angiotensin 2 acts as an AT1 and AT2 receptor agonist
• Role of angiotensin 2:

1) Vasoconstriction
* Angiotensin causes vasoconstriction of renal arteries, which increases total peripheral resistance and constricts blood flow via the kidneys

2) Release of aldosterone
* Angiotensin 2 causes the release of aldosterone from the zona glomerulosa (outermost region) of the adrenal glands, which changes the volume of water excreted from the kidney by increasing Na+ and water reabsorption

3) Stimulation of release of ADH (vasopressin) form the pituitary
* ADH increases blood volume by increasing water permeability in the renal collecting ducts, which decreases urine production

• All of these roles of angiotensin 2 lead to an increase in blood pressure
• The role of the RAAS system is to increase MABP

Question 18

When does low renin hypertension occur?

When can it become secondary?

Where is it more prevalent?

How is it diagnosed?

Answer 18

• Low renin hypertension occurs in a subset of patients with hypertension
• It becomes secondary (caused by another condition) if the cause is known e.g Conn’s syndrome – overproduction of aldosterone
• It is more prevalent in elder individuals and those of Afro-Caribbean descent
• Low renin hypertension is diagnosing using a plasma aldosterone: renin ratio tests, where low renin and abnormal aldosterone indicates low renin hypertension

Question 19

What are 3 circulating factors that contribute to hypertension

Answer 19

• 3 circulating factors that contribute to hypertension:
  1) Endothelin
  2) Nitric Oxide
  3) Reactive oxygen species

Question 20

What is endothelin?

What is the predominant isoform in the CVS?

What can changes in circulation of endothelin be like in hypertension?

What 3 receptors can it bind?

Answer 20

• Endothelin is the most potent vasoconstrictor
• The most common isoform in the CVS is Endothelin-1 (ET1)
• An increase in ET1 circulation is not common in hypertension, but local levels may increase
• Endothelin can bind:
  1) ETA receptors on vascular smooth muscle, causing vasoconstriction
  2) ETA receptors on cardiomyocytes and increase contractility
  3) ETB receptors on endothelial/kidney cells
• This causes production of nitric oxide (NO), which causes vasodilation
• In the kidneys promotes Na+ and H2O excretion (natriuresis and diuresis, respectively)

Question 21

What is nitric oxide (NO)?

What is its half-life like?

Where does NO usually act?

What does it regulate?

Answer 21

• Nitric oxide (NO) is lipophilic gas released from endothelial cells in response to stimuli, and acts as the most potent endogenous vasodilator
• Has a very short half-life
• NO usually acts in tissues where it is secreted
• NO is a chronic regulator of renal blood flow and increases Na+ excretion

Question 22

What 3 things do reactive oxygen species (ROS) include?

How does H2O2 concentration relate to hypertension?

How is it linked with NO?

Does chronic treatment with anti-oxidants help to lower blood pressure?

Answer 22

• Including superoxide, hydrogen peroxide (H2O2) and peroxynitrite
• Patients with essential hypertension have increased circulating H2O2
• ROS in the vasculature may uncouple the enzymes which produce NO
• Chronic treatment with antioxidants does not lower pressure

Question 23

How much do genetics account for BP variance?

Do genetics contribute to hypertension?

Answer 23

• Studies of BP pressure patterns in families suggest genetic factors may account for as much as 30-50% of BP variance
• Whilst many studies have shown associations of gene polymorphisms and BP, the genetic alterations that contribute to primary HT remain elusive
• I.e. there is not a single long gene associated with hypertension

Question 24

What is secondary systemic hypertension?

How many cases of hypertension does it make up?

In what age group does it typically occur in?

What are diseases/situations that cause secondary hypertension?

Answer 24

• Secondary systemic hypertension is high blood pressure that’s caused by another medical condition
• Makes up about 5% of systemic hypertension cases
• Secondary hypertension typically occurs in patients <25 years old
• Diseases/situations that cause secondary hypertension:

1) Renal system diseases

*Renal parenchymal disease:
* Glomerular nephritis,
* Diabetic nephropathy,
* Lupus nephritis,
* Polycystic
* Kidney disease

• Renal vascular:
• Renal artery stenosis
• Vasculitis
• Fibromuscular dysplasia

2) Endocrine system diseases:
* Adrenal gland:
* Zona glomerulosa (increase aldosterone) – Conn’s syndrome
* Zona fasciculata (increased cortisol) – Cushing’s syndrome
* Adrenal medulla (too much epinephrine/norepinephrine) – Pheochromocytoma

3) Pregnancy - Eclampsia, pre-eclampsia (high blood pressures during/after labour)

4) Coarctation of aorta (narrowing)

5) Drugs - Contraceptive pill, cocaine, amphetamine, NSAIDs, alcohol

6) Obstructive sleep apnoea

Question 25

What are 3 consequences on the heart from systemic hypertension?

What are 4 consequences of the vasculature?

What are 3 consequences of the kidneys?

Answer 25

• Consequences of systemic hypertension:

1) Heart
* Heart failure
* Pressure overload from increased TPR, left ventricular hypertrophy
* Myocardial infarction

2) Vasculature
* Accelerated atherosclerosis
* Smaller arteries and arterioles
* Stroke
* Retinopathy

3) Kidneys
* Continued hypertension
* Albuminuria – too much albumin in urine (sign of kidney disease)
* End stage renal disease

Question 26

Consequences of mild, moderate, and severe hypertension on the heart and blood vessels

Answer 26

Consequences of mild, moderate, and severe hypertension on the heart and blood vessels