Session 4 Flashcards
(38 cards)
Describe the fluid compartments in the body and their electrolyte compositions
[*] 2 compartments in the body: ICF and ECF, separated by the cell membrane.
[*] The kidneys are crucial in maintaining both volume and composition of the fluid; this homeostatic maintenance of plasma volume occurs despite varying inputs i.e. drinking lots or being dehydrated, throughout the day.
[*] The ECF volume, which includes the vascular system is determined largely by the concentration of NaCl in this compartment. By regulating the excretion of NaCl, the kidney maintains the volume of the ECF within a very narrow margin.
[*] In the ICF the predominant cation is K+ and in ECF, the predominant cation is Na+
Explain about Sodium Balance
[*] Sodium is the major cation of the ECF and the amount of sodium ions determines the ECF volume (movement of water follows movement of Na+) => determining the volume of plasma, blood volume and hence blood pressure.
[*] On a daily basis, the kidneys must balance the amount of sodium ion excretion so it matches the amount of sodium ion ingestion – this matching process is known as sodium ion balance.
- This avoids the blood pressure changing due to variation of Na+ intake in diet
- Urinary water excretion can be varied physiologically.
[*] Expansion of the ECF: if sodium ion excretion is less than intake then a patient is in positive balance. In this case, extra Na+ ions are retained in the body primarily in the ECF. When the sodium ion content of the ECF increases there is a corresponding increase in ECF volume as water from the nephron is drawn out blood volume and arterial pressure increase and oedema may follow.
Explain about expansion and contraction of the ECF
- Expansion of the ECF: if sodium ion excretion is less than intake then a patient is in positive balance. In this case, extra Na+ ions are retained in the body primarily in the ECF. When the sodium ion content of the ECF increases there is a corresponding increase in ECF volume as water from the nephron is drawn out blood volume and arterial pressure increase and oedema may follow.
- [*] Contraction of the ECF: if sodium ion excretion is greater than ingestion, then a patient is in negative balance. Excess Na+ ions are lost from the body, the Na+ content of the ECF decreases and water remains in the nephron. The ECF volume decreases as does blood volume and arterial pressure.
- [*] NB: we are talking about the total amount of sodium ions not the concentration of the sodium; (you could have a low or high concentration of Na+ depending on the volume of water without affecting the overall Na+ ion amount).
- [*] Changes in sodium ion balance does not affect ECF osmolarity; if the concentration of Na+ ions in the ECF increases the volume increases. This volume expansion results in increased vascular volume and cardiac output. The increase in volume would trigger an increased sodium ion excretion (natriuresis).
Explain about the handling of Sodium ions in the PCT
[*] 100% of Na+ is filtered in the glomerulus, and 67% is reabsorbed in the PCT
[*] This is a proportion of Na+ that is always reabsorbed regardless of the actual amount that is filtered. Autoregulation prevents the glomerular filtration rate from changing too much but if any changes occur despite this, Glomerular Tubular Balance blunts the Na+ excretion response
[*] Na+ reabsorption is mainly active, driven by the 3Na-2K-ATPase basolateral membrane. Different segments of the tubule have different types of Na+ transporters and channels in the apical (luminal) membrane
- Sodium reabsorption is a transcellular process
- Chloride reabsorption is by transcellular (active) and some paracellular (passive) – coupled to 3Na-2K-ATPase pumps.
- Na+ ion reabsorption (chloride is implied)
Describe Chloride reabsorption
- Dependent on sodium reabsorption
- Important to remain electro-neutrality – a finite volume of filtrate must contain equal amounts of anions and cations
- 1 litre of filtrate contains: ~145mM Na+, ~110mM Cl- and ~24mM HCO3-
- PCT reabsorption cations and anions must balance: Na+ = (Cl- + HCO3-)
- HCO3- (90%) is reabsorbed in PCT
- Cl- in PCT reabsorbed ~60%
Explain about reabsorption in S1 of the PCT
Basolateral: 3Na-2K-ATPAse and NAHCO3- co transporter
Apical:
- Co-transported with glucose
- Na-H exchange
- Co-transport with amino acids / carboxylic acids
- Co-transport with phosphate (increased [PTH])
- Aquaporin (water can move through)
- Increased [Urea/Cl-] down S1 compensating for loss of glucose etc creates a concentration gradient for Cl- passive reabsorption in S2/S3
Explain about reabsorption in S2/S3 of the PCT
Section 2/3: Na+ and Water Reabsorption
Basolateral 3Na-2K-ATPase
Luminal Na reabsorbed in S2/S3 via Na-H exchanger
Apical membrane has:
- Na-H exchanger
- Paraceullar Cl- reabsorption
- Transcellular Cl- reabsorption
- Aquaporin
- This sets up an ~4mOsmol gradient favouring water uptake from the lumen
Describe isosmotic reabsorption in the PCT
PCT is highly water permeable which allows reabsorption to be isosmotic with plasma
The reabsorption of water is driven by:
- Osmotic gradient established by solute reabsorption
- Hydrostatic force in Intersticium
- Oncotic force in the peritubular capillary due to the loss of 20% filtrate at the glomerulus, but cells and proteins remained in the blood
In the PCT, there is fast preferential absorption for glucose, amino acids and lactate but Cl- reabsorption lags behind (maintaining osmolarity in the filtrate in the lumen) so osmolarity stays constant despite the solute reabsorption
[*] PCT reabsorption into peritubular capillary
- Proximal tubule highly water permeable
- Tight junctions between tubular cells form a barrier that prevents diffusion of transporter, channel and pump proteins between the apical and basolateral membrane. They maintain the polarity of the tubule cells.
- A bulk transport or obligatory water reabsorption
- PCT reabsorbs 65% of water, 100% of glucose and AA, and 67% of NA
What is the Glomerulotubular Balance?
[*] Autoregulation of GFR prevents GFR from changing too much via myogenic action and tubule-glomerular feedback.
[*] [Glomerulotubular balance is the balance between GFR and the rate of reabsorption of solutes. It must be kept as constant as possible, so if GFR increases, the rate of reabsorption must also increase.
[*] If ECF volume increases, cardiac output will increase causing an increase in arterial blood pressure. This will in turn increase GFR.
[*] 2nd line of defence is the Glomerulotubular response which blunts Na+ excretion response to any GFR changes which do occur despite autoregulation
Describe reabsorption in the loop of Henle (overall)
[*] In the loop of Henle, the reabsorption of solute and water is separated: descending limb reabsorbs water but not NaCl and ascending limb absorbs NaCl but not water.
- The loop of Henle is known as diluting segment as NaCl is diluted in the filtrate.
- Tubule fluid leaving the loop is therefore hypo-osmotic (more dilute) compared to plasma
Describe reabsorption in the Descending Limb
[*] Thin and Thick Descending Limb
The increase in intracellular concentrations of Na+ set up by the PCT allows for the paracellular reuptake of water from the descending limb (NO TIGHT JUNCTIONS).
This concentrates the Na+ and Cl- in the filtrate in the lumen of the descending limb, ready for active transport in the ascending. Chicken and egg who came first?
Describe reabsorption in the Ascending limb
[*] Ascending Limb: IMPERMEABLE to water (tight junctions)
Thin ascending limb: not much active transport occurs
- Sodium reabsorption is passive
- Water reabsorption in descending limb creates a gradient for passive Na+ ion reabsorption in thin ascending limb
- Epithelium in thin ascending limb permits reabsorption by paraceullar route (between the epithelial cells) – there are loose junctions unlike in the thick ascending limb
Thick Ascending Limb (TAL):
- NaCl transported from the lumen into tubule cells by NaKCC2 channel.
- Na+ then moves into the Intersticium due to the action of 3Na-2K-ATPase
- K+ ions diffuse back into the lumen via ROMK (normally ROMK is on the basolateral membrane but here it is on the apical membrane to allow for K+ secretion)
- Cl- ions move into the Intersticium
- In the filtrate in the lumen at this point, there is less K+ ions so in order to maintain activity of the NaKCC2 transporter its vital the K+ ions diffuse back into the filtrate.
- NaKCC2 is the target of loop diuretics (leads to reduced blood volume as increased water excretion however also leads to increased loss of K+ in the urine => hypokalaemia)
The Thick Ascending Limb uses more energy than any other region of the nephron, and is particularly sensitive to hypoxia
Describe Sodium Uptake in the early Distal Tubule
[*] Distal Convoluted Tubule: water permeability of the early DCT is fairly low and the active reabsorption of Na+ results in dilution of the filtrate (inside the tubular cell)
- Hypo-osmotic fluid enters from the lop of Henle and ~5.8% of Na+ is actively transported by the NaCC transporter, driven by 3Na-2K-ATPase
- The NCC transporter is sensitive to Thiazide Diuretics
- The DCT is a major site of calcium reabsorption via PTH.
- This FURTHER DILUTION means the fluid that leaves is more hypo-osmotic
Describe reabsorption in the late DCT and Collecting Duct
In the late DCT and collecting duct, water permeability is variable depending on ADH. Collecting Duct is the region responsible for fine tuning the filtrate. Tubular epithelium is one cell thick in nephron usally all cells sare homologues in a region. It is able to respond to a variety of stimulants and the late DCT and CD have 2 distinct cell types: Principal cells and Intercalated cells
Explain about Principal and Intercalated cells
Principal Cells: 70% of collecting duct cells
- Reabsorb Na+ by Epithelial Na+ Channel (ENaC) on apical which is driven by 3Na-2K-ATPase on basolateral membrane
- Active Na+ ion uptake through a channel and not a cotransporter means there is no accompanying ion
- Produces a negative lumen charge which provides a driving force for Cl- ion uptake via paracellular route.
- The negative luminal charge also has an important role in K+ secretion into the lumen (ROMK present on apical membrane here not basolateral)
- Variable water uptake through Aquaporin 2 (dependent on ADH)
- Have a more distinct membrane than Intercalated cells
Intercalated Cells:
- Active reabsorption of Chloride
- Secrete H+ ions or HCO3-
Describe how changes in pressure affect sodium secretion
- Changes in osmotic pressure and hydrostatic pressure in peritubular capillaries alter the proximal tubule Na+ reabsorption and hence water
- If reduced, they promote Na+ and hence water reabsorption
- If increased they inhibit Na+ and hence water reabsorption
- Proximal tubule Na+ reabsorption is stimulated by RAAS.
- Principal cells of late DCT and CD are targets for the human aldosterone
- ROMK is in thick ascending limb and latter part of DTC and CD on the apical membrane for K+ secretion
Give a summary of fluid and electrolyte balance in the nephron
What are the four neurohormonal factors involved in regulating blood pressure medium and long term?
There are four neurohormonal factors controlling blood pressure in medium and long term. These factors all work in part by controlling sodium balance and thus ECF volume
- Plasma is part of the ECF compartment
- Control of ECF volume controls plasma volume
- Water follows Na+ therefore controlling total body Na+ levels controls plasma volume
- Renin-angiotensin-aldosterone system
- Sympathetic nervous system
- ADH
- ANP
How does the Sympathetic Nervous System regulate blood pressure?
- See CVS module, session 4
- Vasoconstriction by α1-adreoceptors
- Increased force/ rate of heart contraction by β1-adrenoceptors
- High levels of sympathetic stimulation reduce renal blood flow => decreases GFR => decreases Na+ excretion.
- Activates Na/H exchanger in PCT
- Stimulates renin release from juxtaglomerular cells leading to increased Angiotensin II and Aldosterone levels => increased Na+ reabsorption
What is the role of ADH?
- Main role is formation of concentrated urine by retaining water and control plasma osmolarity
- ADH release is stimulated by increases in plasma osmolarity or severe hypovolaemia. Also stimulates Na+ reabsorption by acting on thick ascending limb and stimulating apical NaKCC co-transporter.
What is ANP and what does it do?
The first 3 systems act to preserve blood volume and therefore preserve blood pressure but ANP causes loss of Na+ => reduced blood volume => reduced BP
At least 3 natriuretic hormones have been identified which act to enhance urinary excretion of sodium ions:
Atrial natriuretic peptide (ANP) is secreted by cardiac muscle when NaCl intake is increased and the volume of ECF expands. ANP causes natriuresis but its mechanism of action is uncertain.
- Synthesised and stored in atrial myocytes
- Promotes Na+ excretion in urine via vasodilation of afferent arterioles => increased blood flow increased GFR
- A high BP => stretch in Atrial cells => increased release of ANP => increased Na+ excretion, volume decreases, BP decreases
- A low BP => Atrial cells less stretch => reduce release of ANP => reduced Na+ excretion, volume increases, BP increases.
- Inhibits Na+ reabsorption along the nephron
Natriuetic hormones have also been isolated from the brain (BNP).
[*] Other effects of ANP include:
- Reducing blood pressure
- Decreasing the responsiveness of adrenal glomerulosa cells to stimuli that result in aldosterone production and secretion
- Inhibit secretion of ADH
- Decreasing vascular smooth muscle cell responses to vasoconstrictive agents.
- The latter actions of ANP are counter to the effects of angiotensin II. ANP also LOWERS renin secretion by the kidneys => lowering circulating angiotensin II level
Explain about the baroreceptor reflex
Systemic BP = Co x TPR.
Mean arterial BP = CO x TPR
(Pressure = flow x resistance)
[*] The baroreceptor reflex has an important role in the short term, moment-to-moment regulation of BP by controlling peripheral resistance, heart rate and contractility of the heart. Baroreceptor firing accommodates and thus the setting of the baroreceptors increases in response to prolonged elevation in BP so the baroreceptor reflex works well to control acute changes in BP and produces a rapid response but does not control sustained increases as the threshold for baroreceptor firing resets.
- Adjusts sympathetic and parasympathetic inputs to the heart to alter cardiac output
- Adjust sympathetic input to peripheral resistance vessels to alter TPR
Nerve endings in the carotid sinus and aortic arch are sensitive to stretch; increased arterial pressure stretches these receptors which results in bradycardia and vasodilation to counteract increased mean arterial pressure
What 3 factors influence renin release?
[*] The kidney contributes to the control of the peripheral resistance through the secretion of renin from granular cells of the afferent arteriole in the juxtaglomerular apparatus (JGA). The renin-angiotensin system is a biochemical cascade responsible for the regulation of blood pressure.
[*] 3 factors influence renin release:
- Baroreceptors in afferent arterioles are a key mechanism for regulating renin secretion. A drop in perfusion pressure results in the release of renin from the juxtaglomerular cells of the kidneys
- Renin secretion is also regulated by the rate of Na+ ion and Cl- ion transport across the macula densa; the higher the rate of transport of these ions to the distal tubule, the lower the rate of renin secretion.
Decreased NaCl concentration at the Macula Densa cells (due to low perfusion and therefore low GFR) causes Sympathetic stimulation to the JGA. This also increases the release of renin. Also causes Macula Densa cells to release prostaglandins => afferent arteriole vasodilation.
- Sympathetic stimulation to JGA increases release of renin (JGA = macula dena +granula cells + surrounding mesangial cells)
What does Renin do and what does Angiotensin II do?
[*] Renin, a proteolytic enzyme, cleaves the protein angiotensinogen to form angiotensin I. Angiotensin I is further cleaved by angiotensin-converting enzyme (ACE) to form the active hormone, angiotensin II.
[*] Angiotensin II is a potent vasoconstrictor primarily on the vascular smooth muscle of afferent and efferent arterioles and leads to a rise in both systolic and diastolic pressure (increases TPR and thus BP). Additionally angiotensin II acts on the adrenal cortex to stimulate the synthesis and secretion of aldosterone.
[*] Other physiological responses to angiotensin II includes stimulation of thirst and secretion of ADH via action on the brain and central and peripheral stimulation of the sympathetic nervous system, thus potentiating the release of noradrenaline – angiotensin II enhances sympathetic nervous activity.
- Angiotensin II stimulates Na+ reabsorption in the kidney by stimulating Na+H exchanger in the apical membrane of PCT
- Angiotensin II stimulates ADH release at hypothalamus (stimulating thirst)
- Angiotensin Concerting Enzyme, aka kininase II, breaks down bradykinin (vasodilator)
- Angiotensin II acts largely via G-protein-coupled AT1 receptors. There are also AT2 receptors which are G-protein-coupled
