Urinary S4 (Done) Flashcards
Describe the positive and negative ion composition of the 2 major compartments of the ECF
Plasma:
Positive:
Majority Na+
Some K+, Ca2+, Mg2+
Negative:
Cl- and protein are two biggest components
HCO3- and Pi also present
Interstial fluid:
Positive:
Same as Plasma
Negative:
Proteins mostly absent
Greater proportions of Cl- and Pi result
HCO3- also present
Give an outline of the Ion composition of the ICF
Positive:
Majority K+
Some Na+, Ca2+, Mg+
Negative:
Mostly Pi and Proteins
Some Cl- and HCO3-
What is the major factor affecting ECF volume?
Major osmotically effective ion is Na+
Thus water in ECF depends on Na+ content
What is the effect of Na+ conc change on ECF and BP?
Change in Na+ = change in volume of ECF (increase = increase and vice versa)
Therefore change in Na+ also results in change of the ‘effective circulating volume’
Which in turn is a factor in determining BP
How does the body deal with variable ingestion of Na+ in the diet?
Why is tight control necessary?
Sodium ingestion can vary day to day (0.5g to 20-25g_
Kidney sodium ion excretion rates must vary over a wide range to match ingestion to excretion and maintin Na+ balance
If Na+ ions in ECF where allowed to change with dietary intake:
- Amount of water in ECF would change*
- Thus ECV and BP would change*
Give the amount of Na+ ingested and excreted each day (on average) from different sources
Ingestion:
Food and drink - 10.5g
Excretion:
Urine - 10.0g
Sweat - 0.25g
Faeces - 0.25g
How is control of ECF volume achieved?
Isoosmotic solution must be added or removed to maintain osmolarity
However we have no active water pumps to move water
Therefore osmoles must be moved (E.g Na+) and water will follow
Therefore via manipulation of osmoles the body can add or remove isosmotic amounts of solution to/from the ECF
What proportion of total filtered load of water and Na+ are removed from the nephron at each segment?
Proximal tubule:
67% Na+
65% water
Descending limb of LoH:
0% Na+
10-15% water
Ascending thick and thin LoH:
25% Na+
0% water
DCT:
~5% Na+
0% water
CD:
3% Na+
5% water during water loading
>24% water during dehydration
How is Cl- absorption linked to Na+ absorption?
Cl- absorption dependent on Na+ absorption
Cl- absorption maintains electroneutrality
PCT reabsorption must balance anions and cations
(Na+ = Cl- + HCO3-)
60% of Cl- absorbed in PCT
How much Na+, Cl- and HCO3- does 1 litre of filtrate contain?
145mM Na+
110mM Cl-
24mM HCO3-
What is the basolateral membrane transporter responsible for driving Na+ absorption in the PCT?
Na+/K+ ATPase
In the PCT, what solutes:
- Are preferentially reabsorbed?
- Lag behind the rest?
Why does this occur?
Glucose, AAs and Lactate are preferentially reabsorbed first
Cl- reabsorption lags behind
Reabsorption in the early PCT must be isosmotic with the plasma
Describe the trasnporters present in the S1 segment of the PCT
Basolateral:
Na+/K+ ATPase
NaHCO3- cotransporter
Apical:
Na+/H+ exchange
Co-transporter of Na+ w/glucose
Co-transporter of Na+ w/AAs or carboxylic acids
Co-transporter of Na+ with Phosphate (NaPi channel number sensitive to PTH)
Aquaporins
Describe the involvement of Cl- in S1 of the PCT
S1 largely impermeable to Cl-
Increasing concentration helps maintain osmolarity
Also creates a conc. gradient of Cl- for reabsorption in S2-S3
Describe the transport of ions/water in the S2-3 segments of the PCT
Basolateral:
Na+/K+ ATPase
Apical:
Na+/H+ exchanger
Paracellular and transcellular Cl- absorption
Aquaporins
4mOsmol gradient favouring water reabsorption
Describe the driving forces behind reabsorption into the peritubular capillary
Osmotic gradient established by solute absorption (Increase in osmolarity of interstitium)
Increase in hydrostatic force in the interstitium
Increased oncotic force in the peritubular capillaries due to loss of 20% of plasma volume (increased proportion of proteins and blood cells)
What is glomerulotubular balance in the PCT?
2nd line of defense to prevent or reduce variation in reabsorption of solutes
In practical terms it means that the PCT will always endevour to remove a fixed percentage of solutes from the filtrate
Works to blunt the sodium excretion response to any GFR/Filtered load changes which do occur despite myogenic autoregulation and tubulo-glomerular feedback
E.g. If filtered load of solute rises by 100% then reabsorption rises by 67% of the additional 100% to compensate
Describe the function of the thick and thin descending Loop of Henle
Increase in intercellular concentration of Na+ as the tubule moves into the medulla drives paracellular uptake of water from the descending limb
This concentrates Na+ and Cl- ions in the lumen ready for active transport in the ascending limbs
How permeable is the ascending LoH to water?
Totally impermeable
What is the function of the thin ascending limb of the LoH?
Passive Na+ absorption via paracellular route
What are the transporters present in the thick ascending limb of the loop of henle?
Basolateral:
Na+/K+ ATPase
Cl- channels
Apical:
NaKCC2 transporter
(1Na+, 1K+, 2Cl-)
ROMK
Why is ROMK necessary to the function of the ascending limb of the loop of henle?
In the filtrate at this point there is a low conc of K+ ions so it is vital that K+ ins move back into the lumen to maintain activity of NaKCC2 transporter
Why is the thick ascending limb of the loop of henle particularly sensitive to hypoxia?
Uses more energy than any other region of the nephron
What is the key feature of soute leaving the thick ascending limb of the loop of henle?
Hypo-osmotic compared to plasma
Compare the permeability of the early and late DCT to water
Early - Almost copletely impermeable
Late - Veriable permeability based on ADH concentration
What are the transporters that can be found in a typical DCT cell?
Basolateral:
Na+/K+ ATPase
NCX (Na+/Ca2+ exchange)
Cl- channels
Apical:
NCC transporter (Na+/Cl-)
Ca2+ channels
How is Ca2+ reabsorption in the DCT controlled?
Parathyroid hormone stimulates
What are the functions and cell types of the late DCT?
Responsible for fine tuning of filtrate
Responds to a variety of stimulants
Two types of cell:
Principal cells (70%)
- Reabsorption of Na+ via ENaC
Intercalated cells (30%)
- Active reabsorption of Cl-*
- Secrete H+/HCO3-* (More in acids/bases)
Give the transporters found on principal cells and the relevance of principal cells to other functions in the late DCT/early CD
Basolateral:
Na+/K+ ATPase
Apical:
ENac
K+ channels
Aquaporins
Relevance:
Active uptake of Na+ without accompanying anion creates - luminal charge
Negative charge drives Cl- uptake paracellularly and has a role in K+ secretion into lumen
Aquaporins controlled by ADH (variable H2O absorption)
How is PCT and DCT+CD reabsorption of Na+ controlled?
PCT:
Changes in osmotic pressures and hydrostatic pressure in peritubular capillaries alter PCT reabsorption of Na+ (and hence water)
If increased they inhibit Na+ (and hence water reabsorption) and vice versa
PCT Na+ reabsorption also stimulated by RAAS
DCT+CD:
Principle cells are targets for hormone aldosterone which increases Na+ reabsorption
From CVS:
Give the equation to show mean arterial BP from first principles
Mean arterial BP = (Stroke volume x Heart rate) x TPR
Therefore
Mean arterial BP = Cardiac output x Total peripheral resistance
What is the mechanism for short term regulation of BP?
Baroreceptor reflex
Describe the baroreceptor reflex
Baroreceptor sensitive to stretch found in arch of aorta and carotid sinus
Stretch above threshold leads to afferent nerve stimulus to the medulla
Medulla then increases heart rate and contractility in the heart via increased sympathetic and reduced parsympathetic outflow
Also adjust/lower sympathetic input to peripheral vessels to lower resistance
When below threshold pressure for firing these effects not seen
BP = (SV x HR) x TPR
Why can the baroreceptor reflex not be used to control medium/long term changes?
Threshold for baroreceptor firing is reset (higher) under conditions of long term increased blood pressure
What are the 4 neurohumoral factors in medium/long term control of BP?
What is the common theme of all these methods of control?
RAAS
Sympathetic NS
ADH
Atrial Natriurectic peptide (ANP)
Common:
All act on Na+ levels and hence ECF volume
Describe the factors contributing to the release of renin
Released from Granular cells (found in the afferent arteriole) of the juxtaglomerular apparatus
3 Factors:
Reduced NaCL at the macula densa
Reduced perfusion pressure registered by baroreceptors of afferent arteriole
Sympathetic stimulation of the JGA
Give an overview of the renin-angiotension-aldosterone system (RAAS)
Angiotensinogen cleaved to Angiotensin I by Renin
Angiotensin I cleaved to Angiotensin II by ACE
Angiotensin II acts on AT I and AT II receptors over the body to perform a variety of actions
What are angiotensin II receptors and where are they found?
What is their action at each site?
AT I + II recptors = GPCRs
Main actions via AT I receptors
Arterioles:
Vasoconstriction
Kidney:
Stimulate Na+ reabsorption
Sympathetic NS:
Increased release of NA
Adrenal cortex:
Stimulates release of aldosterone
Hypothalamus:
Increases thirst sensation (Stimulates ADH release)
What are the direct actions of Angiotensin II on the kidney?
Vasoconstriction of the afferent and efferent arteriole (decrease GFR)
Enhaced Na+ absorption via stimulation of Na+/H+ Exchange in PCT
What are the effects of increased aldosterone on the Kidney/
Stimulates water and Na+ reabsorption in the Late DCT and Early CD
Acts on principal cells
Increases expression of ENaC and Apical K+ channel
Also increases basolateral Na+ extrusion via upregulation Na+/K+ ATPase
What are the actions of AE related to control of BP?
Cleaves Angiotensin I to Angiotensin II which has vasoconstricting effects
Also breaks down the vasodilator bradykinin
Double whammy of vasoconstriction
How does the Sympathetic nervous system affect the kidney?
High levels of sympathetic stimulation lead to reduced renal blood flow (decreased GFR and hence Na+ excretion)
Activates apical Na+/H+ exchanger and basolateral Na+/K+ ATPase in PCT
Stimulates renin release from the JGA (RAAS activation)
What are the effects of ADH on the Kidney?
Main role is formation of concentrated urine by retaining water and control of plasma osmolarity
Increases in ADH reduces permeability of the late DCT and early CD to water hence conserving it
Also acts on thick ascending limb of the Loop of Henle (stimulates apical NaKCC2 cotransporter)
What causes the release of ADH?
Increase in plasma osmolarity or severe hypovolaemia
Where is atrial natriuretic peptide synthesised, stored and released from?
Released in response to what?
What inhibits release?
Synthesised, stored and released from:
Atrial myocytes
Released in response to:
Atrial stretch (low pressure volume sensors in the atria)
Inhibition:
Reduced ECV reduces atrial stretch hence inhibits ANP release
What are the effects of ANP on the kidney?
Vasodilation of the afferent arteriole (hence Increased GFR)
Inhibits Na+ reabsorption aong the nephron
What is the importance of Prostaglandins in the kidney?
Release of prostaglandins from the macula densa leads to triggering of the RAAS system(renin release) and hence reduction in GFR and increase in Na+ reabsorption
However
Certain locally acting prostaglandins (Mainly PGE2) enhance GFR (vasodilation of afferent arteriole) and Decrease Na+ reabsorption
They may have an important protective function against overactive SNS and RAAS
What is the clinical relation of prostaglandins and NSAIDs?
NSAIDs inhibit the Cyclo-oxygenase pathway involved in prostaglandin formation
Therefore administration of NSAIDs when renal perfusion is compromised can further decrease GFR and lead to acute renal failure
How is hypertension graded and what are the criteria for each grade?
Mild hypertension:
140-159 systolic
90-99 diastolic
Moderate:
160-179 systolic
100-109 diastolic
Severe:
>180 systolic
>110 diastolic
What are the causes of hypertension?
95% of cases cause unknown (essential hypertension)
When cause can be defined it is known as secondary hypertension
E.g. Renovascular disease, chronic renal disease, aldosteronism, Cushing’s
Important to treat primary cause of secondary hypertension
Describe essential hypertension
No definable cause:
- May be genetically linked (tends to run in families)
Environmental factors
Pathogenesis unclear
Must be above 140/90
What is reno-vascular disease and how does it lead to hypertension?
Occlusion of renal artery leads to decreased perfusion in that kidney
This leads to increase in renin release and hence RAAS activation
Vasoconstriction and Na+ retention result, leading to increased BP
What are the concequences of renal parenchymal disease
Earlier stage may be a loss of vasodilator substances
Late stage Na+ and water retention due to inadequate GFR (volume dependent hypertension)
Give some adrenal causes of hypertension
Conn’s syndrome:
Aldosterone secreting adenoma
Hypertension and hyperkalaemia
Cushing’s:
Excess cortisol secretion
Cortisol at high Conc acts on aldosterone receptors due to high receptor homology (Na+ and water retention)
Phaeochromocytoma:
Tumour of adrenal medulla leading to increased NA and adrenaline relase
NA stimulates Renin release
Why is it important to treat hypertension?
Can be asymptomatic however can have damaging effects on heart/vasculature
Increased afterload:
Heart failure and MI
Arterial damage:
Stroke
Aneurysm
Renal failure
Retinopathy
How can we treat hypertension throught targetting the RAAS?
ACE inhibitors
Reduce Ang II
Therefore diuretic and vasodilator effects
How can we treat hypertension through the use of diuretics?
Thiazide diuretics:
Reduce ECV
Inhibit Na/Cl contransport on apical cells of DCT
Other diuretics:
Aldosterone antagonists will also lower BP
How can we treat hypertension through the use of vasodilators?
L-type Ca channel blockers:
Reduced Ca2+ influx into vascular smooth muscle cells hence relaxation
a1 receptor blockers:
Reduce sympathetic tone in vascular smooth muscle cells hence relaxation
How can we treat hypertension with the use of Beta blockers?
Blocking B1 receptors in the heart will lead to reduced sympathetic effets
Reducing heart rate and contractility
Not a first line treatment
Would be used if there were other indications such as previous MI
What are the non-pharmacological treatments for hypertension?
How eefective are these methods?
Exercise
Diet
Reduce Na+ intake
Reduced Alcohol intake
Effect:
Effects can be limited however failure to implement can limit the effectivness of other antihypertensive therapy
