Urinary Session 4 Flashcards
Describe the osmotic status of sweat.
Hyposmotic
What must happen in order to change plasma volume?
Isosmotic solution must be added or removed so osmolarity remains constant
How is isosmotic volume added or removed from the plasma volume?
Movement of osmoles which water follows
What method of reabsorption does sodium mainly undergo?
Transcellular active driven by 3Na-2K-ATPase on basolateral membrane
In which part of the nephron is movement of water and sodium separated?
Descending thin limb and ascending thin and thick limbs of Henle’s loop
What percentage of sodium in the filtered load is reabsorbed in the PCT?
67
How does the percentage of water and sodium reabsorption from the filtered load in the PCT compare and why?
Approximately equal due to isosmotic reabsorption
What percentage of water in the filtered load is reabsorbed in the ascending limbs of Henle’s loop and the DCT?
0%
What is renal sodium excretion altered by?
Changes in osmotic and hydrostatic pressure in peritubular capillaries
What does an increase in oncotic or hydrostatic pressure in the peritubular capillaries cause?
Inhibition of sodium reabsorption leading to decreased water reabsorption
What is PCT sodium reabsorption stimulated by?
RAAS
What are the target cells for aldosterone?
Principal cells of DCT and CD
What does chloride absorption depend on?
Sodium reabsorption
Why is chloride reabsorption important?
To maintain electroneutrality
What must a finite volume of filtrate contain in terms of ions?
Anions=cations
What main method of reabsorption is used for chloride ions?
Transcellular active coupled to 3Na-2K-ATPase
Is paracellular reabsorption possible with chloride ions?
Yes
Which sodium transporters are found in the PCT tubular cells?
Na-H antiporter
Na-glucose symporter
Na-a.a. cotransporter
Na-Pi PTH transporter
Can the proportions of salts in the filtrate of the PCT vary as long as the osmolarity is constant?
Yes
Why does the proportion of chloride in the filtrate of the PCT increase?
Chloride reabsorption lagers behind so as everything else is removed its relative proportion increases
Why are glucose, a.a. and lactate transporters not needed in the distal PCT?
Fast, preferential reabsorption means that almost 100% is absorbed very quickly
What compensates for loss of glucose in S1 of the PCT to keep osmolarity constant?
Increasing urea and chloride concentration down the segment
What does the compensation of loss of glucose provide for S2-3 of the PCT?
Provide chloride concentration gradient for reabsorption
What type of sodium transporters are seen in S1 of the PCT?
Co transporters
Which sodium transporter is found in the apical membrane along the length of the PCT?
Na-H exchanger
Describe the permeability of the PCT to water.
Very permeable
How is chloride reabsorbed in S2-3 of the PCT?
Intra- and paracellularly
What favours water uptake from the lumen in S2-3 of the PCT?
Presence of oncotic proteins in the peritubular capillaries
What increases uptake into the capillaries surrounding the PCT?
Increased osmolarity of the interstitial spaces
Increased hydrostatic forces in the interstitium
Increased oncotic force from cells and proteins in peritubular capillaries
What is the first line of defence in autoregulation of GFR?
Myogenic action and tubulo-glomerular feedback
Why is the first line of defence in autoregulation of GFR not always sufficient?
Not instantaneous
Not always able to mount a big enough response
What is the second line of defence in maintaining constant GFR via autoregulation?
Glomerulotubular balance to ensure 67% of filtered sodium is reabsorbed regardless of the amount of filtration
What is the benefit of using glomerulotubular balance when GFR has varied widely?
Blunts extreme sodium excretion as a response to GFR changes that have not been corrected so the rest of the tubule can function
What is found between tubular cells of the thick and thin descending limbs of Henle’s loop?
Loose junctions
What is the purpose of increasing intracellular sodium concentration in the thick and thin ascending limbs of Henle’s loop?
Allow paracellular reabsorption of water
What is the purpose of allowing paracellular absorption of water in the thick and thin descending limb of Henle’s loop?
Concentrates sodium and chloride in lumen ready for active transportin the ascending limb
What is found between tubular cells of the thin ascending limb of Henle’s loop?
Tight junctions
What type of sodium reabsorption occurs in the thin ascending limb of Henle’s loop?
Passive paracellular
What is the purpose of ROMK in the apical membrane of thick ascending limb tubular cells?
Leak K+ into the lumen where it is in low concentration in the filtrate so this does not become a limiting factor for reabsorption
Which part of the nephron is most sensitive to hypoxia and why?
Thick ascending limb of Henle’s loop due to high energy demand
Which transporter facilitates sodium reabsorption in the thick ascending limb of the loop of Henle?
NaKCl2
What type of transporter is NaKCl2?
Symporter
What is found between cells of the thick ascending limb of Henle’s loop?
Tight junctions
What type of sodium transporter is found in the apical membrane of the early DCT?
NaCl symporter
Describe the permeability of the early DCT to water.
Low
What is the osmotic state of fluid that enters the early DCT?
Hyposmotic
What is reabsorbed in the early DCT via PTH using an unknown mechanism?
Calcium
How is sodium reabsorbed in the early DCT?
Active transport
What percentage of filtered sodium is reabsorbed in the early DCT?
~5-8%
What is the osmotic state of fluid which exits the early DCT?
More hyposmotic that when it entered
How can cortical and medullary CD cells be distinguished?
Have different transporters
What apical sodium transporter is found in the late DCT and collecting duct tubular cells?
ENaC
Where is the filtrate in the nephron fine tuned in response to a variety of different stimulants?
Late DCT and collecting duct
Which two distinct cell types make up the late DCT and collecting duct?
Principle cells
Type B intercalated cells
What is the ratio of the two types of cells found in the late DCT and collecting duct?
70% principal cells
30% type B intercalated cells
What creates the -ve lumen charge in the late DCT and CD which drives paracellular chloride uptake?
Active Na+ uptake via a channel not cotransporter so no accompanying anion movement
What effect does ADH have on principal cells?
Varies aquaporins for variable water uptake
What is the function of type B intercalated cells?
Active reabsorption of chloride
Secretion of H+/HCO3-
How can type B intercalated cells be distinguished from principal cells on histological examination?
Darker staining nuclei
What system allows increased excretion of sodium and therefore water when increased circulating volume is exerting pressure on the filtration system?
Pressure natriuresis and diuresis
What does an increase in renal after BP cause to happen to transporters in the PCT?
Decreases expression of Na-H antiporter and Na-K-ATPase
What is the result of changes to transporters in the PCT caused by an increase in renal artery BP?
Decreased reabsorption of sodium and water in PCT:
Increased sodium excretion = pressure natriuresis
Increased water excretion = pressure diuresis
Do GFR autoregulation mechanisms still apply in pressure natriuresis and diuresis?
Yes
What in addition to pressure natriuresis and diuresis decreases fluid absorption in an increase of BP?
Increased BP –> increased peritubular capillary pressure –> increased fluid absorption
What is the pressure natriuresis and diuresis system independent of?
Vasomotor activity
Will urine always be isotonic when an isotonic volume is excreted to decrease blood volume?
No
Why do pressure natriuresis and diuresis occur together?
Lack of independent control
What does the degree of pressure natriuresis and diuresis depend on?
Volume status:
Increased ECF = high renal artery BP –> high pressure N&D
Decreased ECF = low renal artery BP –> low pressure N&D
What is the major osmotic ally effective solute in control of effective circulating volume?
Sodium
Where are nerve endings that are sensitive to stretch located which aid in acute regulation of BP?
Carotid sinus
Aortic arch
How do baroreceptors conduct signals to allow for acute regulation of BP?
Baroreceptors –> afferent pathways –> coordinating centre in the medulla –> efferent pathways
How is BP regulated in the short term?
Adjustment of parasympathetic input to peripheral resistance vessels to alter TPR
What happens to baroreceptors in the carotid sinus and aortic arch in long term raised BP?
Baroreceptor firing threshold resets so is still present but not constantly acting
What are the four medium/longer-term mechanisms of BP control?
RAAS
Sympathetic nervous system
ADH
Atrial natriuretic peptide
How does the action of atrial natriuretic peptide (ANP) act differently to the other systems of longer term BP control?
Acts to decreases plasma volume whereas others act to increase
Which fluid compartment is plasma part of?
Extra cellular fluid
How is the RAAS stimulated?
Decreased NaCl to distal tubule
Decreased BP in afferent arteriole
Sympathetic stimulation of beta-1-adrenoceptors
What is released by the macula densa and detected by baroreceptors in the RAAS?
Local mediators
What is the reaction to local mediator detection by baroreceptors in the RAAS?
Renin release from granular cells of the afferent arteriole in the juxtaglomerular apparatus
Where is angiotensinogen synthesised?
Liver
What is angiotensinogen cleaved by?
Renin
What is angiotensinogen cleaved into?
Angiotensin I
What converts angiotensin I to angiotensin II?
Angiotensin converting enzyme
Where is ACE found?
Endothelial cells in non-specific amounts (lots in the lungs)
What additional action does ACE have to its angiotensin converting function?
Breaks down bradykinin into peptide fragments
Why are angiotensin II antagonists sometimes used instead of ACE inhibitors?
To prevent the increase in bradykinin caused by the inhibition of ACE which leads to a dry cough
Which type of angiotensin II receptors carry out the main physiological actions identified with angiotensin II?
AT1
What type of receptor is AT1?
GPCR
At what sites are angiotensin receptors found?
Arterioles Kidney SNS Adrenal cortex Hypothalamus
What does angiotensin II acting on receptors in arterioles cause?
Vasoconstriction
What does angiotensin II acting on receptors in the kidney cause?
Sodium reabsorption
What does angiotensin II acting on receptors in the SNS stimulate?
Increased noradrenaline release
What effects does angiotensin II have on the adrenal cortex and hypothalamus?
Adrenal cortex: increases aldosterone
Hypothalamus: increases thirst –> increases ADH release
How does angiotensin II stimulate sodium reabsorption at the kidney?
Vasoconstriction of afferent and efferent arteriole to decrease GFR
Stimulates NHE3 in apical membrane of principle cell
What is the action of aldosterone release from the adrenal cortex?
Activates apical ENaC and K+ channel
Increases basolateral sodium extrusion via 3Na-2K-ATPase
Why does aldosterone increase receptor expression?
It is a steroid hormone
What effect does increased levels of sympathetic stimulation in the glomerulus have in longer term BP control?
Causes arteriole vasoconstriction –> decrease GFR –> decrease sodium excretion
What is the affect of sympathetic stimulation on the PCT?
Directly activates apical Na/H exchanger and basolateral Na/K-ATPase to increase sodium absorption
What are the effects of renin release stimulated by the sympathetic nervous system?
Increases angiotensin II
Increases aldosterone
Increases sodium reabsorption
What is the main role of ADH?
Control plasma osmolarity
What stimulates ADH release?
1% increase in plasma osmolarity
10% decrease in blood volume
What does ADH act on?
Thick ascending limb to stimulate apical Na/K/Cl co transporter and distal nephron for AQP2 insertion
What is the action of atrial natriuretic peptide?
Promote sodium excretion by inhibiting sodium reabsorption along nephron
How is ANP stored and released?
Synthesised and stored in atrial myocytes and released proportionally to stretch of these
What are low pressure volume sensors?
On low pressure side of circulation e.g. atrial myocytes
What are high pressure volume sensors?
Sensors on the atrial side of the circulation system e.g. baroreceptors
How does a decrease in effective circulation volume inhibit ANP release?
Decreases heart filling –> decreased stretch –> decreased ANP release
What is the effect of ANP on the afferent arteriole?
Causes vasodilation to increase GFR
What is the effect of prostaglandins in the kidney?
Locally enhance GFR and decrease sodium reabsorption by increasing blood flow
What do prostaglandins act as a buffer to to protect renal blood flow?
Excessive vasoconstriction produced by SNS and RAAS when levels of angiotensin II are raised
How can administration of NSAIDs to pts with compromised renal perfusion lead to acute renal failure?
NSAIDs inhibit cyclo-oxygenase pathway so prostaglandins are not synthesised and renal blood flow cannot be protected
How is dopamine formed locally in the kidney?
From L-DOPA
What is the action of dopamine in the kidney?
Acts on receptors on renal blood vessels, cells of PCT and TAL to cause vasodilation and decreased NaCl reabsorption to buffer against excessive vasoconstriction
What action does dopamine have on the transporters of the PCT and TAL?
Inhibits NHE and Na/K/ATPase in principal cells
Can the actions of dopamine in the kidney be used therapeutically?
Dopamine agonists are sometimes used as hypertensives
What is the numerical classification of mild hypertension?
140-159 (+/-) over 90-99
What is the numerical classification of moderate hypertension?
160-179 over 100-109
What is the numerical classification of severe hypertension?
> 180 over >110
What is primary hypertension?
Cause unknown, may be due to genetic/environmental factors
What does recent research suggest is the pathogenesis of primary hypertension?
Dysfunction of dopamine agonist
What are the causes of secondary hypertension?
Renalvascular disease
Renal parenchymal disease
Adrenal causes
How does renalvascular disease cause secondary hypertension?
Renal artery stenosis –> decreased perfusion pressure –> RAAS –> vasoconstriction and sodium retention at the other kidney
How does renal parenchymal disease cause secondary hypertension?
Early stage causes loss of vasodilator substances
Later stage –> inadequate GFR –> sodium and water retention
What is Conn’s syndrome?
Aldosterone secreting adenoma causing hypertension and hypokalaemia
What are the adrenal causes of secondary hypertension?
Conn’s syndrome
Cushing’s syndrome
Phaeochromocytoma
Why does Cushing’s syndrome cause secondary hypertension?
Excess cortisol acts on aldosterone receptors
How does a phaeochromocytoma cause secondary hypertension?
Catecholamines act on beta-1 in kidney and alpha-1 in vasculature and heart
What can arterial damage caused by hypertension lead to?
Atherosclerosis and weakened vessels –> cerbrovascular disease, aneurysm, nephrosclerosis and renal failure, retinopathy
What is often the first visible damage due to hypertension?
Retinopathy
What effects can increased afterload caused by hypertension have?
Left ventricular hypertrophy –> heart failure
Increased myocardial afterload –> myocardial ischaemia and MI
How is secondary hypertension treated?
Identify and treat underlying cause
What methods can be used to treat hypertension?
Targeting RAAS Diuretics Vasodilators Beta-blockers Non-pharmacological approaches
How can the RAAS be targeted to treat hypertension?
ACE inhibitors
Angiotensin II antagonists
How do diuretics treat hypertension?
Reduce circulation and thus decease cardiac output
Give two examples of diuretics that can be used to treat hypertension.
Thiazide Aldosterone antagonists (Spironolactone)
How do thiazide diuretics treat hypertension?
Act in DCT to inhibit Na/Cl co transporter on apical membrane
Are aldosterone antagonists first line treatment for most hypertensive pts?
No
How do vasodilators treat hypertension?
Decrease TPR
How do L-type calcium channel blockers treat hypertension?
Decrease calcium entry into vascular smooth muscle and hence cause relaxation
How do alpha-1-adrenocepetor blockers treat hypertension?
Decrease sympathetic tone thus relaxing vascular smooth muscle
How do beta-blockers treat hypertension?
Decrease cardiac output by decreasing HR and contractility
Are beta-blockers used as a first line hypertension Tx?
No, only if other indications e.g. previous MI or arrythmia
When are non-pharmacological approaches to treating hypertension used exclusively?
Mild hypertension
What non-pharmacological approaches can be used to treat hypertension?
Exercise Diet Decrease sodium intake Decrease alcohol intake Stop smoking
What can limit effectiveness of antihypertensive therapy and lead to more severe hypertension?
Failure to implement lifestyle changes
What is the action of aldosterone release from the adrenal cortex?
Activates apical ENaC and K+ channel
Increases basolateral sodium extrusion via 3Na-2K-ATPase
Why does aldosterone increase receptor expression?
It is a steroid hormone
What effect does increased levels of sympathetic stimulation in the glomerulus have in longer term BP control?
Causes arteriole vasoconstriction –> decrease GFR –> decrease sodium excretion
What is the affect of sympathetic stimulation on the PCT?
Directly activates apical Na/H exchanger and basolateral Na/K-ATPase to increase sodium absorption
What are the effects of renin release stimulated by the sympathetic nervous system?
Increases angiotensin II
Increases aldosterone
Increases sodium reabsorption
What is the main role of ADH?
Control plasma osmolarity
What stimulates ADH release?
1% increase in plasma osmolarity
10% decrease in blood volume
What does ADH act on?
Thick ascending limb to stimulate apical Na/K/Cl co transporter and distal nephron for AQP2 insertion
What is the action of atrial natriuretic peptide?
Promote sodium excretion by inhibiting sodium reabsorption along nephron
How is ANP stored and released?
Synthesised and stored in atrial myocytes and released proportionally to stretch of these
What are low pressure volume sensors?
On low pressure side of circulation e.g. atrial myocytes
What are high pressure volume sensors?
Sensors on the atrial side of the circulation system e.g. baroreceptors
How does a decrease in effective circulation volume inhibit ANP release?
Decreases heart filling –> decreased stretch –> decreased ANP release
What is the effect of ANP on the afferent arteriole?
Causes vasodilation to increase GFR
What is the effect of prostaglandins in the kidney?
Locally enhance GFR and decrease sodium reabsorption by increasing blood flow
What do prostaglandins act as a buffer to to protect renal blood flow?
Excessive vasoconstriction produced by SNS and RAAS when levels of angiotensin II are raised
How can administration of NSAIDs to pts with compromised renal perfusion lead to acute renal failure?
NSAIDs inhibit cyclo-oxygenase pathway so prostaglandins are not synthesised and renal blood flow cannot be protected
How is dopamine formed locally in the kidney?
From L-DOPA
What is the action of dopamine in the kidney?
Acts on receptors on renal blood vessels, cells of PCT and TAL to cause vasodilation and decreased NaCl reabsorption to buffer against excessive vasoconstriction
What action does dopamine have on the transporters of the PCT and TAL?
Inhibits NHE and Na/K/ATPase in principal cells
Can the actions of dopamine in the kidney be used therapeutically?
Dopamine agonists are sometimes used as hypertensives
What is the numerical classification of mild hypertension?
140-159 (+/-) over 90-99
What is the numerical classification of moderate hypertension?
160-179 over 100-109
What is the numerical classification of severe hypertension?
> 180 over >110
What is primary hypertension?
Cause unknown, may be due to genetic/environmental factors
What does recent research suggest is the pathogenesis of primary hypertension?
Dysfunction of dopamine agonist
What are the causes of secondary hypertension?
Renalvascular disease
Renal parenchymal disease
Adrenal causes
How does renalvascular disease cause secondary hypertension?
Renal artery stenosis –> decreased perfusion pressure –> RAAS –> vasoconstriction and sodium retention at the other kidney
How does renal parenchymal disease cause secondary hypertension?
Early stage causes loss of vasodilator substances
Later stage –> inadequate GFR –> sodium and water retention
What is Conn’s syndrome?
Aldosterone secreting adenoma causing hypertension and hypokalaemia
What are the adrenal causes of secondary hypertension?
Conn’s syndrome
Cushing’s syndrome
Phaeochromocytoma
Why does Cushing’s syndrome cause secondary hypertension?
Excess cortisol acts on aldosterone receptors
How does a phaeochromocytoma cause secondary hypertension?
Catecholamines act on beta-1 in kidney and alpha-1 in vasculature and heart
What can arterial damage caused by hypertension lead to?
Atherosclerosis and weakened vessels –> cerbrovascular disease, aneurysm, nephrosclerosis and renal failure, retinopathy
What is often the first visible damage due to hypertension?
Retinopathy
What effects can increased afterload caused by hypertension have?
Left ventricular hypertrophy –> heart failure
Increased myocardial afterload –> myocardial ischaemia and MI
How is secondary hypertension treated?
Identify and treat underlying cause
What methods can be used to treat hypertension?
Targeting RAAS Diuretics Vasodilators Beta-blockers Non-pharmacological approaches
How can the RAAS be targeted to treat hypertension?
ACE inhibitors
Angiotensin II antagonists
How do diuretics treat hypertension?
Reduce circulation and thus decease cardiac output
Give two examples of diuretics that can be used to treat hypertension.
Thiazide Aldosterone antagonists (Spironolactone)
How do thiazide diuretics treat hypertension?
Act in DCT to inhibit Na/Cl co transporter on apical membrane
Are aldosterone antagonists first line treatment for most hypertensive pts?
No
How do vasodilators treat hypertension?
Decrease TPR
How do L-type calcium channel blockers treat hypertension?
Decrease calcium entry into vascular smooth muscle and hence cause relaxation
How do alpha-1-adrenocepetor blockers treat hypertension?
Decrease sympathetic tone thus relaxing vascular smooth muscle
How do beta-blockers treat hypertension?
Decrease cardiac output by decreasing HR and contractility
Are beta-blockers used as a first line hypertension Tx?
No, only if other indications e.g. previous MI or arrythmia
When are non-pharmacological approaches to treating hypertension used exclusively?
Mild hypertension
What non-pharmacological approaches can be used to treat hypertension?
Exercise Diet Decrease sodium intake Decrease alcohol intake Stop smoking
What can limit effectiveness of antihypertensive therapy and lead to more severe hypertension?
Failure to implement lifestyle changes
