Download PowerPoint - Pitt Honors Human Physiology

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Silverthorn 19-2
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If we are denied water, we need to excrete less
If we drink a lot of water, we need to excrete more
(while still excreting the appropriate amounts of various solutes)
If water moves only by diffusion, how can this be accomplished?
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Figure 28-1 Water diuresis in a human after ingestion of 1 liter of water.
Note that after water ingestion, urine volume increases and urine
osmolarity decreases, causing the excretion of a large volume of dilute
urine; however, the total amount of solute excreted by the kidneys
remains relatively constant. These responses of the kidneys prevent
plasma osmolarity from decreasing markedly during excess water
ingestion
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If water can’t follow the
solute, then excess water
relative to solute can get
excreted
X
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If water can’t follow the solute,
then excess water relative to
solute can get excreted
This transporter is a Na-K-2Cl
transporter, which is very
active in the ascending limb of
the loop of Henle
As a result, can excrete
~20L/day of 50 mOsm/L urine
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Loop of Henle Sodium Reabsorption – thick ascending limb
Ascending Thick Limb of the
Loop of Henle Epithelial Cell
Tubular Lumen
Capillary Lumen
(blood)
(urine)
Na+
2K+
ATP
3 Na+
2 ClK+
K+ recycling
K+
+
Na+ Ca+2 Mg+2
Cl-
ROMK
channel
-
Paracellular Pathway
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or 4
Adding water channels back into the collect duct, would allow some of that
water to get reabsorbed, and that’s what ADH (or vasopressin) does
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Germann 18.10
A slightly different version of the previous slide:
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A slightly more complicated version of the previous slide:
Brown D, et al, Traffic. 2009 Mar;10(3):275-84. Sensing, signaling and
sorting events in kidney epithelial cell physiology.
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Section of kidney collecting duct triple-immunostained to show AQP2 (green) and AQP4 (red) in vasopressinsensitive principal cells, and the proton-pumping V-ATPase (blue) in acid-secreting intercalated cells. In the region
of the kidney shown here, the inner stripe of the outer medulla, A-IC express V-ATPase apically. In response to
systemic acidosis, V-ATPase pumps accumulate in the apical plasma membrane and proton secretion is activated
to help excrete the acid load (Bar = 5 μm).
Brown D, et al, Traffic. 2009 Mar;10(3):275-84. Sensing, signaling and sorting events in kidney epithelial cell
physiology.
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Kidney collecting duct
AQP4
AQP2
V-ATPase
PC
IC
H+
H2O
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ADH is made in the hypothalamus
(paraventricular and supraoptic
nuclei) and released from the
posterior pituitary
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Hyperosmolarity sensed by osmoreceptors:
•Central osmoreceptors (hypothalamic)
•Hepatic portal osmoreceptors ??
Hypovolemia
•Atrial baroreceptors
Hypotension
•Arterial baroreceptors
?? Role of angiotensin
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Brain osmoreceptors are neurons that are endowed with an intrinsic ability to
detect small changes in ECF osmolality
a | MRI images in the horizontal (upper image) and sagittal (lower image)
planes, highlighting areas that show a significantly increased blood-oxygenlevel-dependent (BOLD) signal under conditions in which thirst was
stimulated in a healthy human by infusion of hypertonic saline. The arrows
point to increased BOLD signals in the anterior cingulate cortex (ACC; lefthand arrow) and in the area of the lamina terminalis (right-hand arrow) that
encompasses the organum vasculosum laminae terminalis (OVLT). b |
Plots showing changes in thirst (upper plot) and changes in the BOLD
signals in voxels of interest in the ACC (middle plot) and the lamina
terminalis (lower plot) of the subject imaged in part a. The values of plasma
osmolality shown in the upper plot represent average changes that were
observed in a group of subjects that all underwent the same treatment. The
traces show that osmoreceptors in the OVLT stay activated as long as
plasma osmolality remains elevated, whereas the activation of cortical
areas correlates with the sensation of thirst. c | Frequency plots showing
examples of changes in firing rate that were detected during extracellular
single-unit recordings obtained from three OVLT neurons in superfused
explants of mouse hypothalamus. d | A scatter plot showing the changes in
firing rate (relative to baseline) that were recorded from many mouse OVLT
neurons during the administration of hyperosmotic stimuli of various
amplitudes. The data indicate that osmoreceptor neurons in the OVLT
encode increases in extracellular fluid osmolality through proportional
increases in firing rate. This plot only shows data from osmoresponsive
neurons (approximately 60% of the total neuronal population in the OVLT).
Part a modified, with permission, from Ref. 27 ©(2003) National Academy
of Sciences. Part b modified, with permission, from Ref. 27 © (2003)
National Academy of Sciences and Ref.197 © (1999) National Academy of
Sciences. Parts c and d reproduced, with permission, from Ref. 89 ©
(2006) Society for Neuroscience.
C.W. Bourque. Nature Reviews Neuroscience 9, 519-531 (July 2008)
Central mechanisms of osmosensation and systemic osmoregulation
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Two actions of ADH:
Antidiuretic
Action on kidney
Very sensitive (1-15 pM
Action on V2 receptors to cause insertion of
aquaporin 2 into epithelial cell members in the
collecting ducts
Vasopressor
Higher concentrations required than for antidiuresis
Action on V1 receptors in arterioles
(discrepancy between vasocontrictor and
vasopressor effects)
Figure 28-9 Neuroanatomy of the hypothalamus, where antidiuretic
hormone (ADH) is synthesized, and the posterior pituitary gland, where
ADH is released.
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Effect of drinking on mean ± SE values of plasma osmolality
(Posmol; A), plasma vasopressin (pVP;B), and plasma oxytocin
(pOT; C) in rats infused with 1 M NaCl (2 ml/h iv for 240 min).
This slide from a study we conducted on
osmoregulation in rats is included to make
two points :
 While we typically think about negative
feedback reflexes, feedforward control is
important too!
 And then there is this issue with oxytocin:
what does it do?
Wan Huang et al. Am J Physiol Regul Integr Comp Physiol
2000;279:R756-R760
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Diabetes Insipidus
•Central – problem with ADH synthesis or secretion
•Nephrogenic – problem with renal response to ADH
~20 L/day of a very hypotonic urine (~ 50 mOsm/L)
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Insipidus = Latin for lacking taste
How can we make a urine that’s more concentrated than 300 mOsm/L?
and we can: ~ 1200 mOsm/L !!
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Germann 18.9
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The ascending limb of the loop of Henle pumps solute, but is
impermeable to water
The adjacent descending limb of the loop of Henle is permeable to
water but does not transport solute.
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Silverthorn 19-4
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Germann 18.9
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Silverthorn 19-10
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Figure 28-4 Formation of a concentrated urine when antidiuretic hormone
(ADH) levels are high. Note that the fluid leaving the loop of Henle is dilute
but becomes concentrated as water is absorbed from the distal tubules
and collecting tubules. With high ADH levels, the osmolarity of the urine is
about the same as the osmolarity of the renal medullary interstitial fluid in
the papilla, which is about 1200 mOsm/L. (Numerical values are in
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milliosmoles per liter.)
Figure 28-5 Recirculation of urea absorbed from the medullary collecting duct into
the interstitial fluid. This urea diffuses into the thin loop of Henle, and then passes
through the distal tubules, and finally passes back into the collecting duct. The
recirculation of urea helps to trap urea in the renal medulla and contributes to the
hyperosmolarity of the renal medulla. The heavy dark lines, from the thick
ascending loop of Henle to the medullary collecting ducts, indicate that these
segments are not very permeable to urea. (Numerical values are in milliosmoles
per liter of urea during antidiuresis, when large amounts of antidiuretic hormone
are present. Percentages of the filtered load of urea that remain in the tubules are
indicated in the boxes.)
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Figure 28-7 Changes in osmolarity of the tubular fluid as it passes through
the different tubular segments in the presence of high levels of antidiuretic
hormone (ADH) and in the absence of ADH. (Numerical values indicate the
approximate volumes in milliliters per minute or in osmolarities in
milliosmoles per liter of fluid flowing along the different tubular segments.)
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Notice that even in the presence of
maximal ADH, some water is lost:
obligate water loss. Consider that
we cannot make a urine that is
more concentrated than ~1200
mOsm/L and that there is a certain
amount of organic waste that
needs to be excreted in the urine,
~600 mOsm per day. Thus, under
those conditions, the minimal urine
volume would be 0.5 L/day. (Note
that the calculations don’t quite
work out with the values presented
in this figure.)
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Negative feedback loop controlling plasma osmolality.
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Negative feedback loop controlling plasma osmolality.
What about feedforward regulation?
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Note the difference in threshold for
VP secretion and thirst.
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Figure 28-11 Effect of large changes in sodium intake on extracellular fluid sodium
concentration in dogs under normal conditions (red line) and after the antidiuretic
hormone (ADH) and thirst feedback systems had been blocked (blue line). Note that
control of extracellular fluid sodium concentration is poor in the absence of these
feedback systems.
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Diabetes Mellitus: Large volume of glucose-containing urine
Why is there glucose in the urine?
Why is urine volume increased?
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