The Renal System Flashcards
1
Q
What does the renal (urinary) system include?
A
Renal (urinary) system includes kidneys, ureters, bladder and urethra.
2
Q
What is the main role of the kidney?
A
Kidneys process the plasma portion of blood by removing
substances from it, and in a few cases, by adding substances to it.
3
Q
Basic anatomy of the Renal System
A
NOTION 1.1
4
Q
What are some other functions of the kidneys?
A
- Regulation of H2O and inorganic ion balance: regulation of ECF volume and composition. Most important function of the kidney. Includes regulation of Na+, K+, Ca2+, Mg2+, Cl-, HCO3-, H+, phosphates and sulphates.
- Removal of metabolic waste products from the blood and their excretion in the urine. Urea from protein breakdown, uric acid, creatinine from muscle creatine breakdown, breakdown products of Hb.
- Removal of foreign chemicals from the blood and their excretion in the urine (food additives, drugs, pesticides).
- Gluconeogenesis (synthesis of glucose from amino acids)
- Production of hormones (endocrine functions)
5
Q
What are 3 examples of hormones released from the kidneys?
A
- Erthryopoetin, which enhances erythrocyte production during hypoxia by acting on bone marrow. Anaemia occurs in patients with renal disease.
- Renin, an enzyme that controls formation of angiotensin and influences BP and Na+ balance
- 1,25-dihydroxyvitamin D (calcitriol), which influences Ca2+ balance
6
Q
Location/ Structure of the kidneys
A
• The kidneys are paired organs lying in the posterior abdominal wall on either side of the vertebral column.
• Covered in a tough fibrous capsule.
• In gross structure, the kidneys are divided into an outer granular cortex and an inner striated medulla
NOTION 1.2
7
Q
- What is the nephron?
- How many nephrons are there in the 2 kidneys?
- Components of a nephron
A
- The nephron is the basic unit of the kidney.
- There are a total of about 2.5 million in the 2 kidneys.
- Each nephron consists of 2 functional components, a tubular component and a vascular component
8
Q
Structure of a nephron
A
NOTION 1.3
9
Q
Epithelium of the tubule of a nephron
A
Throughout its course, tubule is composed of a single layer of epithelial cells which differ in structure from portion to portion in relation to the function of the different parts.
10
Q
Where does the tubular component of a nephron originate?
A
It originates in a blind sac, Bowman’s capsule, which is
intimately associated with the glomerulus on one side.
11
Q
What is the first part of the tubule (of a nephron)?
What is the epithelium like here?
How is the surface area of this section increased?
A
- First part of tubule = The highly coiled proximal convoluted tubule.
- Here the epithelial cells are wide and contain many
mitochondria. - The surface area is greatly increased by numerous
projections (microvilli) on the luminal surface, forming a
brush border.
12
Q
- What does the proximal tubule drain into?
- What is the epithelium like here?
- How does the loop of henle ascend back to the cortex?
A
- The proximal tubule drains into the thin descending limb of the Loop of Henle.
- Epithelial cells are flattened and thin, with few mitochondria.
- They make sharp hairpin-like turns, and ascend back
towards the cortex as thin ascending limbs of the Loop of
Henle, which becomes the thick ascending limb. This has
numerous mitochondria.
13
Q
What does the Loop of Henle pass into?
A
The Loop of Henle passes into the distal tubule. The distal tubule of 1 nephron connects with those of other nephrons to form a collecting duct.
14
Q
What do the collecting ducts drain into?
A
Collecting ducts draining more nephrons anastomose throughout the cortex and medulla until they eventually drain into the renal pelvis, which is continuous with the ureter which leads to the bladder.
15
Q
What do nephrons with glomeruli in the outer part of the cortex have?
What about those in the juxtamedullary region?
A
Nephrons with glomeruli in the outer part of the cortex
have short Loops of Henle, whilst those with glomeruli in
the juxtamedullary region of the cortex have long loops
which extend down to the medullary pyramids.
16
Q
Proportion of cortical and juxtamedullary nephrons
A
The proportion of cortical and juxtamedullary nephrons
varies greatly among different species. In humans, 15-
20% of the nephrons are of the juxtamedullary type.
17
Q
What does blood enter the kidney via?
What does this branch into?
A
• Blood enters kidney via renal artery
• Divides into smaller branches which penetrate cortex
• Each small artery branches at right angle to form afferent arterioles, each of which leads to a compact node of capillaries, the glomerulus, which protrude into Bowman’s capsule
18
Q
Juxtaglomerular apparatus
A
NOTION 1.4
19
Q
How are glomerular capillaries unique in the body?
A
They recombine to form another arteriole, the efferent arteriole, which then divides up again to form a 2nd set of capillaries, peritubular capillaries. These are intimately associated with the remaining portions of the tubule.
20
Q
In juxtamedullary nephrons, what do peritubular capillaries show?
A
In juxtamedullary nephrons, peritubular capillaries show
a modification; they form hairpin-like loops, the vasa
recta, which dip into the medulla in parallel with the
Loops of Henle. These capillaries ultimately drain into
venous channels by which blood leaves the kidney in the
renal vein.
21
Q
Junction between peritubular capilllary & nephron tubule
A
NOTION 1.5
22
Q
Endothelium lining the glomerular capillaries
A
Endothelium lining glomerular capillaries is fenestrated,
showing pores (40-90nm).
Too large to restrain plasma constituents, but expose glomerular basement membrane to free flow of plasma by removing endothelial barrier. The basement membrane does act as a morphological barrier to passage of plasma
proteins.
23
Q
What is the visceral layer of Bowman’s capsule organised into?
A
• Visceral layer of Bowman’s capsule organised into
specialised cells (podocytes) which carry negative
charge. This repels negatively-charged plasma proteins
i.e. an electrostatic barrier
• Therefore barriers to filtration are greatly reduced
(except for protein)
24
Q
Water makes up ______ of body weight
A
60%
25
Average daily water balance in an adult male
NOTION 1.6
26
Structure of a nephron
NOTION 2.1/2.2
27
What are the 4 processes of the kidneys?
The four processes of the kidney are:
- Filtration: Movement from blood to lumen
- Reabsorption: From lumen to blood
- Secretion: From blood to lumen
- Excretion: From lumen to outside the body
NOTION 2.3
28
What processes are undertaken at the renal corpuscle (glomerulus & Bowman’s Capsule)?
Filtration of mostly protein-free plasma from the capillaries into the capsule
29
What processes are undertaken at the proximal tubule?
Isosmotic reabsorption of organic nutrients, ions, and water. Secretion of metabolites and xenobiotic molecules such as penicillin.
30
What processes are undertaken at the loop of henle?
Reabsorption of ions in excess of water to create dilute fluid in the lumen. Countercurrent arrangements contributes to concentrated interstitial fluid in the renal medulla.
31
What processes are undertaken at the distal nephron (distal tubule & collecting duct)?
Regulated reabsorption of ions and water for salt and water balance and pH homeostasis.
32
Structure of the renal corpuscle
NOTION 2.4
33
What are podocytes?
Podocyte foot processes surround each capillary, leaving slits through which filtration takes place. Mesangial cells between the capillaries contract to alter blood flow.
NOTION 2.5
34
What helps create a three layer filtration barrier in the renal corpuscle?
The glomerular capillary endothelium, basement membrane, and podocytes create a three layer filtration barrier. Filtered susbtances pass through endothelial pores and filtration slits.
NOTION 2.6
35
Renal handling of the following substances:
- Na+ ions
- Cl- ions
- K+ ions
- Ca2+ ions
- Glucose
- Urea
- PAH
In the proximal tubule, ascending loop of henle and distal nephron. What % is excreted?
NOTION 2.7
36
How can the amount of solute excreted be calculated?
Amount Filtered - Amount reabsorbed + Amount secreted = Amount of solute excreted
I.e F - R + S = E
37
What is a “normal” glomerular filtration rate?
The glomerular filtration rate (GFR) is very high = 125 mls/min = 180 l/day. This means that the kidney has ample opportunity to precisely regulate ECF volume and composition and eliminate “nasty” substances.
38
How does glomerular filtration take place?
What is glomerular filtration dependent on?
Glomerular Filtration occurs in exactly the same way as fluid filters out of any capillary in the body. It is dependent on the balance between the hydrostatic forces favouring filtration and the oncotic pressure forces favouring reabsorption (Starling’s forces).
Overall GFR is determined by:
- Filtration pressure
- Filtration coefficient (Slit surface area & filtration barrier permeability)
39
How can net filtration pressure be calculated?
Ph - Pi - Pfluid = net filtration pressure
Ph = Hydrostatic pressure (blood pressure)
Pi = Colloid osmotic pressure gradient due to proteins in plasma but not in Bowman’s capsule
Pfluid = Fluid pressure created by fluid in Bowman’s capsule
NOTION 2.8
40
What does P_GC & P_PC stand for?
P_GC = Hydrostatic pressure in glomerular capillary
P_PC = Hydrostatic pressure in peritubular capillary
41
Relationship between P_GC and Pi at the glomerulus
P_GC >> Pi
Must be this way at glomerulus (filtration), but different in peritubular capillaries (reabsorption).
42
What % of plasma that passes through the glomerulus is filtered?
Only 20% of the plasma that passes through the glomerulus is filtered. Less than 1% of filtered fluid is eventually excreted.
43
What factors affect GFR?
In normal physiology, 1° factor is P_GC and this is dependent on the afferent and efferent arteriolar diameter and therefore the balance of resistance between them.
Subject to extrinsic control via:
a) Sympathetic VC nerves → afferent and efferent constriction
b) Circulating catecholamines → constriction
c) Angiotensin II → constriction, of efferent at [low], both
afferent and efferent at [high].
NOTION 2.9
44
Autoregulation of GFR
Renal vasculature also exhibits a well developed intrinsic ability to adjust its resistance in response to changes in arterial BP and thus to keep BF and GFR essentially constant = autoregulation.
45
In humans, what is autoregulation of GFR effective over?
In humans, effective over a range of MBP from 60-130mmHg. Below 60mmHg, filtration falls and ceases altogether when MBP = 50mmHg.
46
Starlings forces in the peritubular capillaries
The low P_PC and the high Pi is that the balance of Starling’s forces in the peritubular capillaries is entirely in favour of reabsorption.
47
What % of the following are reabsorbed within the tubule?
- H2O
- Glucose
- Na+ ions
- Urea
99% H2O, 100% glucose, 99.5% Na+, 50% urea filtered at the glomerulus are reabsorbed within the tubule, largely at the proximal convoluted tubule.
48
How are many susbtances reabsorbed in the kidneys?
What do these transporters have?
Many substances are reabsorbed by carrier mediated
transport systems eg glucose, amino acids, organic acids, sulphate and phosphate ions.
Carriers have a maximum transport capacity (Tm) which is due to saturation of the carriers. If Tm is exceeded, then the excess substrate enters the urine.
49
To what degree is glucose filtered in the kidneys?
At what [plasma glucose] will all glucose be reabsorbed?
What happens beyond this level?
1. Glucose is freely filtered, so whatever its [plasma] that will be filtered.
2. In humans for plasma glucose up to 10 mmoles/l, all will be reabsorbed. Beyond this level of plasma [glucose], it appears in the urine = Renal plasma threshold for glucose.
50
How much glucose is filtered, reabsorbed and excreted, if [plasma glucose] = 15 mmoles/l ?
If plasma [glucose] = 15 mmoles/l, 15 will be filtered, 10
reabsorbed and 5 excreted.
51
How are solutes reabsorbed in the tubules?
1. Na+ is reabsorbed by active transport
2. Electrochemical gradient drives anion reabsorption
3. Water moves by osmosis, following solute reabsorption. Concentrations of other solutes increases as fluid volume in lumen decreases.
4. Permeable solutes are reabsorbed by diffusion through membrane transporters or by the paracellular pathway
NOTION 2.10
52
What is involved in sodium linked reabsorption?
What solutes are absorbed by Na-linked cotransport?
Na+ enters the tubule cells by co-transport, then is actively pumped out of the basolateral side by the Na+/K+ ATPase. Solutes that are absorbed by Na-linked cotransport include:
- Glucose
- Amino acids
- Other organic solutes
- Some ions such as phosphate & sulfate
NOTION 2.11
53
What is the transport rate of a substance proportional to?
What is the renal threshold?
The transport rate of a substance is proportional to the plasma concentration of the substrate, up to the point at which transporters become saturated. Once saturation occurs, transport rate reaches a maximum.
The plasma concentration of substrate at which the transport maximum occurs is called the renal threshold.
NOTION 2.12
54
Graphs displaying filtration, reabsorption & excretion of glucose in the kidneys
NOTION 2.13
55
Where are Na+ ions most abundant?
What does this mean?
How many moles of Na+ ions are filtered each day?
What % of Na+ ions are reabsorbed each day?
Na+ ions are the most abundant in the ECF, a very large
amount are filtered every day. 180 l/day x 142 mmoles/l =
25560 mmoles/day, 99.5% is reabsorbed.
56
Where does the majority of Na+ ion reabsorption take place? What % takes place here?
By what mechanism is Na+ reabsorbed?
Therefore what does this require?
65-75% of Na+ ion reabsorption occurs in the proximal tubule. Not reabsorbed by a Tm mechanism, but by active transport, which establishes a gradient for Na+ across the tubule wall. Active transport requires ATP!
57
Diagram of transport of Na+ across the apical & basolateral membrane
NOTION 3.1
58
Can substances such as inulin and mannitol cross the tubular membrane? What is the effect of this?
For some substances eg inulin and mannitol, the tubular membrane is impermeable, so fluid stays in side tubule – can use as tracers or diuretics.
59
Is urea excreted or reabsorbed?
What is the effect of this?
Urea – excrete some but keep ~50% to concentrate the interstitium –enhances reabsorption of other molecules and ions.
60
What is the effect of anything that decreases active transport?
It is the active transport of Na+ that establishes the gradients down which other ions, H2O and solutes pass passively. Anything which decreases active transport e.g. decreases BF → disruption of renal function.
61
Are Tm - limited carrier mediated secretory mechanisms known for some substances?
Yes, Tm-limited carrier-mediated secretory mechanisms are known for a large number of endogenous as well as exogenous substances such as drugs.
62
Are carrier mechanisms specific?
What is the effect of this?
• Carrier mechanisms are not very specific so that e.g. organic acid mechanism, which secretes lactic and uric acid can also be used for substances such as penicillin, aspirin and PAH (para-amino-hippuric acid).
• Similarly, organic base mechanism for choline, creatinine etc, can be used for morphine and atropine.
• All of these substances are secreted at the proximal tubule
63
Mechanisms involved in Organic anion secretion
1. Direct active transport: The Na+-K+-ATPase keeps intracellular Na+ low
2. Secondary indirect active transport. The Na+-dicarboxylate cotransporter (NaDC) concentrates a dicarboxylate inside the cell using energy stored in the Na+ gradient
3. Tertiary indirect active transport. The basolateral organic anion transporters concentrate organic anions inside the cell, using the energy stored in the dicarboxylate gradient.
4. Organic anions enter the lumen in exchange for a dicarboxylate
NOTION 3.2
64
How important are K+ ions?
What is normal ECF[K+] ?
What happens if this increases?
What happens if this decreases?
• K+ is the major cation in the cells of the body and the maintenance of K+ balance is essential for life. Normal ECF[K+] = 4mmoles/l.
• If it increases to 5.5mmoles/l = hyperkalaemia → decreases resting membrane potential of excitable cells and eventually ventricular fibrillation and death. Remember the Nernst equation!
• If [K+] < 3.5 mmoles/l = hypokalaemia → increases resting membrane potential ie hyperpolarizes muscle, cardiac cells and nerves → cardiac arrhythmias and paralysis and eventually death.
65
Where is K+ (which is filtered at the glomerulus) primarily reabsorbed?
K+ filtered at the glomerulus is reabsorbed, primarily at the proximal tubule.
66
What are changes in K+ excretion due to?
Changes in K+ excretion are due to changes in its secretion in the distal parts of the tubule. Any increase in renal tubule cell [K+] due to increased ingestion will stimulate K+ secretion, while any decrease in intracellular [K+] will reduce secretion.
67
What hormone regulates K+ secretion?
In addition, K+ secretion is regulated by the adrenal cortical hormone aldosterone. An increase in [K+] in ECF bathing the aldosterone secreting cells stimulate aldosterone release which circulates to the kidneys to stimulate increase in renal tubule cell K+ secretion.
68
Effect of aldosterone on Na+ reabsorption
Aldosterone also stimulates Na+ reabsorption at the distal
tubule but by a different reflex pathway.
69
What is involved in H+ secretion in the kidney?
H+ secretion: H+ ions are actively secreted from the tubule
cells (not the peritubular capillaries) into the lumen
70
Equations for the following:
- Excretion
- Filtration rate (of X)
- Excretion rate (of X)
- Clearance (of X)
NOTION 3.3
71
Diagram displaying renal clearance of inulin vs glucose
NOTION 3.4
72
Diagram displaying renal clearance of urea vs penicillin
NOTION 3.5
73
Osmolarity, Osmolality, Tonicity & Effective Osmoles
Osmolarity is the number of osmoles of solute per litre of solution:
- Osmolarity depends on the volume of the solution, and therefore on the temperature and pressure of the solvent
Osmolality is the number of osmoles of solute per kilogram of solvent:
- Osmolality depends on the mass of the solvent which is independent of temperature and pressure.
Tonicity is the osmotic pressure between two compartments, and is related to the difference in the concentration of "effective" osmoles between them.
Effective osmoles are those substances which are unable to penetrate the membrane between compartments, and therefore they are effective in their contribution to the osmotic pressure gradient.
74
What is a hypertonic solution?
If a solution has a higher concentration of solutes (less water) than another it is said to be hypertonic.
75
Osmolarity of fluid leaving the proximal tubule, compared to that of the plasma.
Why is this the case?
The fluid that leaves the proximal tubule is isosmotic
with plasma ie 285 mOsmoles/l.
This is because all the solute movements are accompanied by equivalent H2O movements, so that osmotic equilibrium is maintained.
76
Maximum concentration of urine
Maximum concentration of urine that can be produced by the human kidney = 1200-1400mOsmoles/l ie 4x more
concentrated than plasma = excess of solute over water.
77
What substances must be excreted each day?
How many osmoles do these total to?
Therefore, how much water is required to do so?
The urea, sulphate, phosphate, other waste products and nonwaste ions (Na+ and K+) which must be excreted each day amount to around 600 mOsmoles. This therefore requires a minimum obligatory H2O loss of 500mls.
78
Osmolarity changes of the fluid throughout the nephron
NOTION 4.1
79
How concentrated can urine be in desert species?
Desert species can produce urine as concentrated as
6000mOsmole/l, all H2O needs can be met by metabolic
H2O.
80
What is the minimum urine concentration in humans?
In conditions of excess H2O intake, H2O is excreted in
excess of solute, minimum [urine] in humans is 30-50
mOsmoles/l ie 10 fold dilution compared with plasma.
81
How are kidneys able to produce urine of varying concentration?
Kidneys are able to produce urine of varying concentration
because the loops of Henle of juxtamedullary nephrons act as countercurrent multipliers. Countercurrent is easy, fluid flows down the descending limb and up the ascending limb.
82
What are the 2 critical characteristics of the loops of Henle, which make them countercurrent multipliers?
The critical characteristics of the loops which make them
countercurrent multipliers are:
1. The ascending limb of the loop of Henle actively cotransports Na+ and Clions out of the tubule lumen into the interstitium.The ascending limb is impermeable to H2O.
2. The descending limb is freely permeable to H2O but relatively impermeable to NaCl.
83
Diagram of the basics of the Countercurrent Multiplier
NOTION 4.2
84
More complex diagram of the Countercurrent Multiplier
NOTION 4.3
85
Countercurrent exchange in the Vasa Recta
NOTION 4.4
86
What has the countercurrent multiplier achieved?
1. Concentrates fluid on the way down and promptly re-dilutes it on the way back up, NOT by adding H2O, but by removing NaCl.
2. One consequence of this is that 15-20% of the initial filtrate (up to 36 l) is removed from the loop of Henle.
3. Fluid which enters the distal tubule is more dilute than
plasma.
87
What is the effect of the overwhelming significance of the CC multiplier?
- The overwhelming significance of the countercurrent
multiplier is that it creates an increasingly concentrated
gradient in the interstitium.
- Only a 200 mOsm gradient exists at any horizontal level, but its effect is multiplied by the countercurrent flow.
88
What is the Vasa Recta?
What would happen if the medullary capillaries drained straight through?
Permeability of the vasa recta
The Vasa Recta: The specialized arrangement of the peritubular capillaries of the juxtamedullary nephrons also participate in the countercurrent mechanism by acting as countercurrent exchangers.
If medullary capillaries drained straight through they would
carry away the NaCl removed from the loop of Henle and
abolish the interstitial gradient. Does NOT happen because they are arranged as hairpin loops and therefore do not interfere with the gradient
As with all capillaries, the vasa recta are freely permeable to
H2O and solutes and therefore equilibrate with the medullary interstitial gradient.
89
What are the 3 main functions of the Vasa Recta?
1. Provide O2 for medulla.
2. In providing O2 must not disturb gradient.
3. Removes volume from the interstitium, up to 36l/day. The balance of Starling’s forces are very much in favour of reabsorption because of high Pi, and high Pt due to tight renal capsule which drives fluid into capillaries.
90
Blood flow rate through Vasa Recta
The flow rate through the vasa recta is very low so that there is plenty of time for equilibration to occur with the interstitium, further ensuring that the medullary gradient is not disturbed.
91
Where is the site of water regulation?
What hormone is involved?
The site of water regulation is the Collecting duct, whose
permeability is under the control of ADH = Anti-Diuretic
Hormone (Vasopressin).
92
What is the effect of ADH (Anti-Diuretic Hormone)?
• Increases the permeability of the collecting ducts to H2O,
by incorporating H2O channels into the luminal membrane.
• If ADH is present then H2O is able to leave the collecting
duct.
• Helps you reabsorb water when dehydrated, low BP, loss
of blood volume etc.
93
Diagram displaying effect of ADH (Vasopressin)
NOTION 4.5
94
Mode of Action of ADH
NOTION 4.6
95
How does ADH cause insertion of water pores into the apical membrane?
1. ADH binds to membrane receptor
2. Receptor activates cAMP second messenger system
3. Cell inserts AQP2 water pores into apical membrane
4. Water is absorbed by osmosis into the blood
96
Characteristics of ADH:
- Origin
- Chemical Nature
- Transport in the circulation
- Half-life
- Factors affecting release
- Target cells or Tissues
- Receptor/ Second Messenger
- Tissue Action
- Action at Cellular-molecular level
Origin: Hypothalamic neurons in paraventricular and supraoptic nuclei. Released from posterior pituitary
Chemical Nature: 9 amino acid peptide
Transport in the circulation: Dissolved in plasma
Half-life: 15 minutes
Factors affecting release: Increased Osmolarity (Hypothalamic osmoreceptors) & Decreased Blood Pressure (Carotid, Aortic, Atrial Receptors)
Target cells or Tissues: Renal Collecting Duct
Receptor/ Second Messenger: V2 Receptor/ cAMP
Tissue Action: Increases renal water reabsorption
Action at Cellular-molecular level: Inserts AQP water pores in apical membrane
97
Diagram displaying control of ADH Secretion
NOTION 4.7
98
Effect of high levels of ADH
• If [ADH] is high produce a small volume of highly
concentrated urine, which contains relatively less of the
filtered H2O than of solute, therefore compensating for water deficit.
• Effectively adds pure H2O to the ECF. H2O is reabsorbed by the oncotic P of vasa recta, which will be even greater than usual in the presence of the H2O deficit.
99
Effects of absence of ADH
• In the absence of ADH, collecting ducts are impermeable
to H2O, so that water cannot get out of the collecting duct
and re-enter the bloodstream
• Therefore a large volume of dilute urine is excreted,
compensating for H2O excess. Since further ions are
reabsorbed from the CD, urine osmolarity can fall to 30-50
mOsm/l.
100
Role of Urea in controlling concentration of urine
• Role of urea: plays an important part in the production of
concentrated urine.
• In the presence of ADH, movement of H2O out of the CDs
greatly concentrates the urea remaining in the ducts.
101
What is ADH (Vasopressin) also known as?
Arginine vasopressin
102
What is the primary control of ADH secretion?
What are changes in neuronal discharge mediated by?
Some suggest that these receptors also mediate?
How is a change in osmolarity detected by these receptors?
Primary control is plasma osmolarity: When the effective OP of the plasma increases, the rate of discharge of ADH-secreting neurones in the SO and PVN is increased → increased release of ADH from the posterior pituitary.
Changes in neuronal discharge are mediated by osmoreceptors in the anterior hypothalamus, close to the SO and PVN.
Other receptors in the lateral hypothalamus mediate thirst.
(Some suggestion that they may even be the same
osmoreceptors that affect ADH, although location uncertain).
Changes in the volume of the osmoreceptors → changes in
osmoreceptor discharge. (Stretch-sensitive ion channels).
103
Effect of an increase in osmolarity, with no change in tonicity, on ADH secretion
An increase in osmolarity that does not cause an increase in tonicity is ineffective in causing an increase in [ADH].
NOTION 4.8
104
Sensitivity and response of osmoreceptors with regards to changes in osmolality
Normal plasma osmolality is 280-290mOsm/kg H2O. It is regulated very precisely. Small changes in either direction results in rapid changes in ADH. System has a very high “gain” a 2.5% increase in osmolality can produce a 10x increase in ADH.
105
Graph displaying [ADH] against mOsm/kg H2O
NOTION 5.1
106
Effects of ECF Volume on ADH Secretion
• Increased ECF volume → Decreased [ADH]
• Decreased ECF volume → Increased [ADH]
107
Relationship between ADH Secretion & Discharge from stretch receptor
There is an inverse relationship between the rate of ADH secretion and the rate of discharge of stretch receptor afferents in the low and high P areas of the circulation.
108
Where are Low Pressure receptors located?
What are they sometimes called?
Low P receptors are located in the L and R atria and great
veins. They are sometimes called “volume receptors” because they monitor the return of blood to the heart and the “fullness” of the circulation.
109
Where are High Pressure receptors located?
High P receptors are the carotid and aortic arch baroreceptors.
110
What do moderate decreases in ECF Volume primarily affect?
Moderate decreases in ECF volume 1°ily affect the atrial receptors. Normally they exert tonic discharge of ADH secreting neurones via the vagus nerve. Decreased ECF volume → Decreased atrial receptor discharge and hence increased ADH release.
111
What happens if volume changes enough to affect MBP?
If volume changes enough to affect MBP, then carotid (and aortic) receptors will also contribute to changes in ADH secretion. Very important in haemorrhage. Even when going from lying down to standing up, there is an increase in ADH release.
112
What are some other stimuli that affect ADH?
Other stimuli affecting ADH:
• Increased ADH: Pain, emotion, stress, exercise, nicotine, morphine. Following traumatic surgery, inappropriate ADH secretion occurs, need to be careful about monitoring H2O intake.
• Decreased ADH: Alcohol, suppresses ADH release.
• Diabetes Insipidus: ADH deficiency
113
Homeostatic response to salt ingestion
NOTION 5.2
114
Diagram of the Renin-Angiotensin System (RAS)
NOTION 5.3
115
With regard to Angiotensin II:
- Origin
- Chemical nature
- Biosynthesis
- Transport in the circulation
- Half life
- Factors affecting release
- Control Pathway
- Target Cells or Tissues
- Receptor
- Tissue function
- Origin: Inactive precursor protein angiotensin made by the liver
- Chemical nature: 8 amino acid peptide
- Biosynthesis: Angiotensinogen -> (Renin) -> Angiotensin I -> (ACE) -> Angiotensin II
- Transport in the circulation: Dissolved in plasma
- Half life: 1 min (renin half life = 10-20 mins)
- Factors affecting release: Decreased Blood Pressure
- Control Pathway: Renin-Angiotensin System
- Target Cells or Tissues: Adrenal Cortex, Arterioles, Brain
- Receptor: AT Receptors
- Tissue function: Adrenal cortex secrete aldosterone. Arterioles vasoconstrict. Medulla oblongata reflexes to increase blood pressure. Hypothalamus secrete vasopressin and increase thirst.
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What is the primary action of aldosterone?
Renal sodium reabsorption
NOTION 5.4
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With regard to Aldosterone:
- Origin
- Chemical nature
- Biosynthesis
- Transport in the circulation
- Half life
- Factors affecting release
- Target Cells or Tissues
- Receptor
- Tissue action
- Action at cellular level
- Origin: Adrenal cortex, Zona glomerulosa
- Chemical nature: Steroid
- Biosynthesis: Made on demand
- Transport in the circulation: 50-70% bound to plasma protein
- Half life: 15 minutes
- Factors affecting release: Decreased Blood Pressure. Increased Potassium aka hyperkalemia. Natriuretic peptides inhibit release!
- Target Cells or Tissues: Renal collecting duct
- Receptor: Cytosolic mineralcorticoid (MR) Receptor
- Tissue action: Increases Na+ reabsorption and K+ secretion
- Action at cellular level: Synthesis of new ion channels (ENaC and ROMK) and pumps (Na+-K+-ATPase); increased activity of existing channels and pumps
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The pressure-volume graph for normal human bladder
NOTION 5.5
119
What is micturition?
Micturition aka urination
120
Stages of micturition
1. Stretch receptors fire
2. Parasympathetic neurons fire. Motor neurons stop firing
3. Smooth muscle contracts. Internal sphincter is passively pulled open. External sphincter relaxes
NOTION 5.6
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Local spinal reflex involved in urination
1. As the bladder fills with urine, stretch receptors are stimulated and increase their discharge →
2. Inhibition of detrusor (bladder) muscle and opening of the internal sphincter as well as relaxation of the external sphincter and micturition occurs.
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How does micturiton occur in babies?
What is involved in voluntary control as an adult?
In babies, this local spinal reflex is how micturition occurs and also in patients with spinal cord transection.
Voluntary control over external sphincter is learnt during
“potty” training. Can delay emptying up until a point.
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Alkalosis vs acidosis
• Loss [H+] > Gain [H+] = ALKALOSIS = pH more than 7.4
• Gain [H+] > Loss [H+] = ACIDOSIS = pH less than 7.4
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What systems/ organs help control acid base balance?
Kidneys are major controllers of acid-base balance, along with the respiratory system.
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pH balance in the body
NOTION 6.1
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What are different sources of H+ gain?
• Generation of H+ from CO2 in blood
• Production of non-volatile acids from metabolism of protein and other organic molecules (e.g. lactic, phosphoric, sulphuric acids)
• Gain of H+ due to loss of HCO3- (bicarbonate) in diarrhoea or other non-gastric GI fluids
• Gain of H+ due to loss of HCO3- in urine
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What are different sources of H+ loss?
• Use of H+ in metabolism of various organic anions
• Loss of H+ in vomit (loss of HCl, so less H+, but more HCO3- than plasma)
• Loss of H+ in urine (kidneys can remove H+ from plasma or add them)
• Hyperventilation (blow off more acidic CO2)
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Respiratory compensation for metabolic acidosis
NOTION 6.2
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What happens to the intercalated cells, during acidosis?
Acidosis: Type A intercalated cells in collecting duct function in acidosis. H+ is excreted; HCO3- and K+ are reabsorbed.
NOTION 6.3
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What happens to the intercalated discs during alkalosis?
Alkalosis: Type B intercalated cells in collecting ducts function in alkalosis. HCO3- and K+ are excreted; H+ is reabsorbed.
NOTION 6.3
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Reabsorption of bicarbonate in the proximal tubule
1. NHE3 secretes H+
2. H+ in filtrate combines with filtered HCO3- to form CO2
3. CO2 diffuses into cell
4. CO2 combines with water to form H+ and HCO3-
5. H+ is secreted again
6. HCO3- is reabsorbed with Na+
7. Glutamine is metabolised to ammonium ion and HCO3-
8. NH4+ is secreted and excreted
NOTION 6.4
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Renal responses to acidosis
• H+ ions secreted to reabsorb all filtered HCO3-
• Even more H+ secreted, contributing new HCO3- to plasma as these H+ ions are excreted bound to non-HCO3- urinary buffers such as HPO4^2-
• Tubular glutamine metabolism and ammonium excretion
are enhanced to make more HCO3- (TAKES TIME!!!)
• NET RESULT: More new HCO3- into blood, increasing
plasma [HCO3-]. This compensates for the acidosis. Urine is
highly acidic (lowest pH is 4.4)
NOTION 6.5
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Renal responses to alkalosis
• Rate of H+ secretion is inadequate to reabsorb all filtered HCO3-
• HCO3- is excreted in urine, but little or no H+ excretion on
non-HCO3- urinary buffers
• Tubular glutamine metabolism and ammonium excretion
are decreased, so little or no HCO3- is added to the plasma from this source
• NET RESULT: Decreased HCO3- in plasma compensates for the alkalosis. Urine is alkaline (pH > 7.4)
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Normal blood values:
- pH
- [HCO3-]
- PCO2
Normal blood values:
- pH = 7.4
- [HCO3-] = 24 mM
- PCO2 = 40 mmHg/ 5.33 kPa
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Chronic vs acute acid base disorders
Metabolic disorders are always chronic, so usually have enough time to alter [HCO3-]. With respiratory disorders, they can be acute or chronic. Only the chronic ones will have enough time to cause a marked change in [HCO3-].
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What are the different types of acid-base disorders?
Give an example of a condition which causes each of these acid base disorders.
• Metabolic acidosis - diabetic ketoacidosis
• Metabolic alkalosis - prolonged vomiting
• Acute resp. acidosis - breathing 7% CO2
• Chronic resp. acidosis - emphysema
• Acute resp. alkalosis - hyperventilation
• Chronic resp. alkalosis - prolonged residence at altitude
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What are the 3 steps involved in diagnosing acid-base disorders?
1. Is it an ACIDOSIS or an ALKALOSIS? We use the pH for this!
2. Is the cause METABOLIC or RESPIRATORY in nature
- If the HCO3- value explains the problem, then it must be metabolic as these ions are part of your metabolism and are handled by your kidneys.
- If the CO2 value explains the problem, then the problem is respiratory as you breathe CO2.
3. Is this a CHRONIC (long-term) problem or an ACUTE (short-term) problem? (The HCO3- helps you with this as it takes a long time to use up lots of HCO3- or to start manufacturing lots of new HCO3-. A good rule of thumb is that, if the HCO3- value is 5 or more mmol/l away from 24 mmol/l, then it is CHRONIC. If it is very close to the 24 mmol/l value, then it is likely to be ACUTE.).
