Week 4 - Volume and blood pressure control Flashcards
1
Q
How can sodium ions affect blood pressure?
A
- Sodium is the major cation of the ECF
- The amount of Na+ determines the ECF volume
- In turn, this determines the volume of plasma and hence blood pressure
2
Q
What causes expansion of the extracellular fluid?
A
- If Na+ excretion is less than intake, then a patient is in positive sodium balance
- Extra Na+ ions are retained in the body, primarily in the ECF
- When Na+ content of the ECF increases, there is a corresponding increase in ECF volume
- – Water from the nephron is drawn out
- – Blood volume and arterial pressure increase
- – Oedema may follow
3
Q
What causes contraction of the extracellular fluid?
A
- If sodium ion excretion is greater than ingestion, then a patient is in negative sodium balance
- Excess Na+ is lost from the body
- The Na+ content in the ECF decreases
- – Water remains in the nephron
- – Decrease in ECF volume
- – Blood volume and arterial pressure decrease
4
Q
What happens to Na+ ions in the PCT?
A
- 100% of the Na+ is filtered in the glomerulus
- 67% is reabsorbed in the PCT
- – This percentage is always reabsorbed, regardless of the actual amount that is filtered (glomerular tubular balance)
- Na+ reabsorption is mainly active
- – Driven by 3Na-2K-ATPase pumps on the basolateral membrane
- Different segments of the tubule have different types of Na+ transporters and channels in the apical membrane
5
Q
What happens at different points of the PCT and what channels are found there?
A
Section 1 of the PCT: - Na+ is cotransported with glucose - Na-H exchange - Co-transport with AA/carboxylic acids - Co transport with phosphate - Aquaporin - [Urea and Cl-] increase down this section, compensating or the loss of glucose - Increasing [Cl-] creates a concentration gradient for chloride reabsorption Section 2/3 of the PCT: - Na+ and water reabsorption - Na-H exchanger - Paracellular Cl- reabsorption - Transcellular Cl-reabsorption - Aquaporin
6
Q
What type of reabsorption occurs in the PCT?
A
Isosmotic reabsorption:
- The PCT is highly water permeable
- Allows reabsorption to be isosmotic with plasma
- Reabsorption is water is driven by:
- – Osmotic gradient due to solute reabsorption
- – Hydrostatic force in the interstitium
- – Oncotic force in the peritubular capillary (Due to the loss of 20% filtrate at the glomerulus, but cells and proteins remained in the blood)
7
Q
What is the glomerulotubular balance?
A
The balance between GFR and the rate of reabsorption of solutes
- Must be kept as constant as possible
- If GFR increases, the rate of reabsorption must also increase
- It blunts sodium excretion
- It is a response to any GFR changes that occur despite autoregulation
8
Q
What happens if the ECF volume increases?
A
- Cardiac output will increase
- This will cause an increase in arterial pressure
- This in turn will increase GFR
9
Q
What happens in the descending limb?
A
It reabsorbs water but not NaCl
- The increase in intracellular concentrations of Na+ set up by the PCT allows for paracellular reuptake of water
- This concentrates the Na+ and Cl- in the lumen of the descending limb, ready for active transport in the ascending limb
10
Q
What happens in the ascending limb?
A
It reabsorbs NaCl but not water
- Known as the diluting segment
- Tubule fluid leaving the loop is hypo-osmotic compared to plasma
- Impermeable to water, as it has tight junctions
- Thin ascending limb:
- – Sodium reabsorption is passive and occurs paracellularly
- – The gradient is created by water reabsorption in the descending limb
- Thick ascending limb:
- – NaCl is transported from the lumen into the cells by NaKCC2
- – Na+ then moves into the interstitium due to the action of 3Na-K-ATPase
- – K+ ions diffuse back into the lumen via ROMK
- – Cl- ions move into the interstitium
- – This region uses more energy than any other region of the nephron and is particularly sensitive to hypoxia
- – NaKCC2 is the target of loop diuretics
11
Q
What happens in the early DCT?
A
- Water permeability is fairly low
- The active reabsorption of Na+ results in dilution of the filtrate
- Hypo-osmotic fluid enters from the loop
- ~5-8% of Na+ is actively transported by the NaCC transporter, driven by 3Na-2K-ATPase
- – This transporter is sensitive to thiazide diuretics
- The DCT is also a major site of calcium reabsorption, via PTH
- The fluid that leaves is more hypo-osmotic than the fluid that entered
12
Q
What cells are found in the later DCT/collecting duct?
A
There are 2 distinct cell types:
- Principle cells
- – 70% of the cells
- – Reabsorption of Na+ via epithelial Na+ channel (ENaC)
- – Driven by 3 Na-2K-ATPase
- – Provides lumen charge
- – Electrical gradient for paracellular Cl- reabsorption
- – Potassium secretion into the lumen
- – Variable water uptake via aquaporin 2
- – Dependent on ADH
- Type B intercalated cells
- – Active reabsorption of chloride
- – Secrete H+ ions or HCO3-
13
Q
What are the 4 neurohumoral factors controlling blood pressure?
A
- Renin-angiotensin-aldosterone system
- Sympathetic nervous system
- Antidiuretic hormone
- Atrial natriuretic peptide
14
Q
How does sympathetic stimulation affect blood pressure?
A
High levels of sympathetic stimulation reduce renal blood flow
- Vasoconstriction of arterioles by α1-adrenoceptors
- Increases force/rate of heart contraction β1-adrenoceptors
- Decrease GFR and hence Na+ excretion
- Activates Na/H exchanger in PCT
- Stimulates renin release
(Raises BP)
15
Q
How does atrial natriuretic peptide affect blood pressure?
A
- Promote Na+ excretion
- Synthesised and stored in atrial myocytes
- Released from atrial cells in response to stretch
- Reduced effective circulating volume inhibits the release of ANP
— Less filling of the heart so less stretch and hence less ANP released so BP can be maintained - Causes vasodilation of the afferent arteriole
(Lowers BP)
16
Q
How does dopamine affect blood pressure?
A
- Formed locally in the kidney from circulating L-Dopa
- Dopamine receptors are present on renal blood vessels and cells of the PCT and thick ascending limb
- Causes vasodilation and increases renal blood flow
- Reduces reabsorption of NaCl
— Inhibits Na/H exchanger and Na/K-ATPase in principal cells of the PCT and thick ascending limb
(Lowers BP)
17
Q
How is renin released?
A
Released from granular cells of juxtaglomerular apparatus
- Release may be stimulated by:
- – Reduced NaCl delivery to distal tubule
- – Detected by macula densa cells
- – Reduced perfusion pressure in the kidney
- – Detected by baroreceptors in the afferent arteriole
- – Sympathetic stimulation to the juxtaglomerular apparatus
18
Q
What are the actions of angiotensin II?
A
- Vasoconstriction
- – Works on vascular smooth muscle cells, increasing TPR ergo BP
- – Vasoconstriction of afferent and efferent arteriole
- Aldosterone
- – Stimulates the adrenal cortex to synthesise and release aldosterone
- – Aldosterone stimulates Na+ and hence water reabsorption
- – Acts on principal cells of collecting duct
- – Activates ENaC and apical K+ channels
- – Increases basolateral extrusion via 3Na-2K-ATPase
- Sympathetic activity
- Increase Na+ reabsoprtion
- Thirst
- Breaks down bradykinin
- – Bradykinin has vasodilatory effects
19
Q
What is the renin-angiotensin-aldosterone system?
A
- Renin stimulates the conversion of angiotensinogen to angiotensin I
- Angiotensin I can be converted to angiotensin II by angiotensin converting enzyme
- Angiotensin II can (amongst other things) stimulate the release of aldosterone
20
Q
Describe angiotensin II receptors
A
- AT1 and AT2
- Main actions are via AT1 receptor
- They are G-protein coupled receptors
- Sites + actions:
- – Arterioles = vasoconstriction
- – Kidney = stimulates Na+ reabsorption at the kidney
- – Sympathetic nervous system = increased release of noradrenaline
- – Adrenal cortex = stimulates release of aldosterone
- – Hypothalamus = increases thirst sensation
21
Q
What stimulates ADH release?
A
- Increase in plasma osmolarity
- Severe hypovolaemia
22
Q
What does ADH do?
A
- Formation of concentrated urine by retaining water to control plasma osmolarity
- – Increases water reabsorption in the distal nephron, by addition of aquaporins to collecting duct
- It stimulates Na+ reabsorption
- – Acts on the thick ascending limb
- – Stimulates apical NaKCC2
23
Q
What do prostaglandins do?
A
- Act as vasodilators
- Locally acting prostaglandins enhance glomerular filtration and reduce Na+ reabsorption
- Help to maintain renal blood flow and GFR
- Act as a buffer to excessive vasoconstriction process by the RAA system
- – Important protective function
24
Q
How can NSAIDS interfere with prostaglandins?
A
- Inhibit cyclo-oxygenase pathway
- – This is involved in the production of prostaglandins
- If administered when renal perfusion is compromised, GFR can be further decreased leading to acute renal failure
25
Q
What is hypertension?
A
A sustained increase in blood pressure
- In 95% of cases the cause is unknown
- – Essential/primary hypertension
- – No definable cause
- – May be due to genetic factors or environmental factors
- Where the cause can be defined it is referred to as secondary hypertension
- – E.g. renovascular disease, chronic renal disease, Cushing’s syndrome
- – Important to treat the cause
26
Q
What are some causes of secondary hypertension?
A
- Renovascular disease:
— Occlusion of the renal artery causes a fall in perfusion pressure in that kidney
• This leads to increased renin production
• Activation of RAAS
• Vasoconstriction and Na+ retention at other kidney - Adrenal causes:
— Conn’s syndrome
• Aldosterone secreting adenoma
• Hypertension and hypokalaemia
— Cushing’s syndrome
• Excess secretion of cortisol (a glucocorticoid)
• At high concentrations, it can act on aldosterone receptors - Pheochromocytoma
• Tumour of the adrenal medulla
• Secretes noradrenaline and adrenaline
27
Q
How can you treat hypertension?
A
- ACE inhibitors
- – Prevent the production of angiotensin II from angiotensin I
- – Angiotensin II receptor antagonists
- Thiazide diuretics
- – Inhibit NaCC co-transporter on apical membrane of DCT
- – May cause hypokalaemia
- Vasodilators
- – Ca2+ channel blockers; reduce Ca2+ entry into smooth muscle cells
- – α1-receptor blockers, reduce sympathetic tone
- Beta blockers (theoretically)
- – Block β1-receptors in the heart
- – Reduces heart rate and contractility
- Non-pharmacological approaches:
- – Diet
- – Exercise
- – Reduced Na+ intake
- – Reduced alcohol intake
