DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

For maximum concentration of urine, large amounts of urea
must be deposited in the interstitium of the inner medulla. It is not surprising,
therefore, that V 2
-receptor activation also increases urea permeability
by 400% in the terminal portions of the inner medullary
collecting duct. V 2
receptors increase urea permeability by activating
a vasopressin-regulated urea transporter (termed VRUT, UT1, or UT-
A1), most likely by PKA-induced phosphorylation (Sands, 2003).
Kinetics of vasopressin-induced water and urea permeability differ,
and vasopressin-induced regulation of VRUT does not entail vesicular
trafficking to the plasma membrane (Inoue et al., 1999).
In addition to increasing water permeability of the collecting
duct and urea permeability of the inner medullary collecting duct,
V 2
-receptor activation also increases Na + transport in thick ascending
limb and collecting duct. Increased Na + transport in thick ascending
limb is mediated by three mechanisms that affect the
Na + -K + -2C1 − symporter: rapid phosphorylation of the symporter,
translocation of the symporter into the luminal membrane, and
increased expression of symporter protein (Ecelbarger et al., 2001).
Enhanced Na + transport in collecting duct is mediated by increased
expression of subunits of the epithelial Na + channel (Ecelbarger et
al., 2001). The multiple mechanisms by which vasopressin increases
water reabsorption are summarized in Figure 25–22.
Rapid decrease
in inner
medullary
blood flow
Increased
medullary
osmolality
Rapid activation
of VRUT in apical
membrane of IMCD
V 1a Receptor
Rapid activation
of Na + –K + –2Cl –
symporter to apical
membrane of TAL
Rapid translocation
of Na + –K + –2Cl –
symporter to apical
membrane of TAL
Long-term increase
in expression of
Na + –K + –2Cl –
symporter in TAL
Vasopressin
V 2 Receptor
Long-term increase
in expression of
aquaporin-2
in principal cells of
collecting duct
Rapid insertion of
preformed aquaporin-2
into apical membrane
of principal cells
in collecting duct
Increased permeability of
collecting duct to water
Renal conservation of water
Figure 25–22. Mechanisms by which vasopressin increases the
renal conservation of water. Red and black arrows denote major
and minor pathways, respectively. IMCD, inner medullary
collecting duct; TAL, thick ascending limb; VRUT, vasopressinregulated
urea transporter.
Renal Actions of Vasopressin. Several sites of vasopressin
action in kidney involve both V 1
and V 2
receptors
(Bankir, 2001). V 1
receptors mediate contraction
of mesangial cells in the glomerulus and contraction of
vascular smooth muscle cells in vasa recta and efferent
arteriole. V 1
-receptor-mediated reduction of inner
medullary blood flow contributes to the maximum concentrating
capacity of the kidney (Franchini and
Cowley, 1996) (Figure 25–22). V 1
receptors also stimulate
prostaglandin synthesis by medullary interstitial
cells. Since PGE 2
inhibits adenylyl cyclase in collecting
duct, stimulation of prostaglandin synthesis by V 1
receptors may counterbalance V 2
-receptor-mediated
antidiuresis. V 1
receptors on principal cells in cortical
collecting duct may inhibit V 2
-receptor-mediated water
flux by activation of PKC. V 2
receptors mediate the
most prominent response to vasopressin, which is
increased water permeability of the collecting duct.
Indeed, vasopressin can increase water permeability in
collecting duct at concentrations as low as 50 fM. Thus,
V 2
-receptor-mediated effects of vasopressin occur at
concentrations far lower than are required to engage
V 1
-receptor-mediated actions. This differential sensitivity
may not be due to differences in receptor affinities
because cloned rat V 1a
and V 2
receptors have
similar affinities for vasopressin (K d
= 0.7 and 0.4 nM,
respectively) but rather may be due to differential
amplification of their signal-transduction pathways.
The collecting-duct system is critical for water conservation.
By the time tubular fluid arrives at the cortical collecting duct, it has
been rendered hypotonic by the upstream diluting segments of the
nephron that reabsorb NaCl without reabsorbing water. In the wellhydrated
subject, plasma osmolality is in the normal range, concentrations
of vasopressin are low, the entire collecting duct is relatively
impermeable to water, and the urine is dilute. Under conditions of
dehydration, plasma osmolality is increased, concentrations of vasopressin
are elevated, and the collecting duct becomes permeable to
water. The osmotic gradient between dilute tubular urine and hypertonic
renal interstitial fluid (which becomes progressively more
hypertonic in deeper regions of the renal medulla) provides for
osmotic flux of water out of the collecting duct. The final osmolality
of urine may be as high as 1200 mOsm/kg in humans, and a significant
saving of solute-free water thus is possible.
Other renal actions mediated by V 2
receptors include
increased urea transport in inner medullary collecting duct and
increased Na + transport in thick ascending limb; both effects contribute
to the urine-concentrating ability of the kidney (Figure
25–22). V 2
receptors also increase Na + transport in cortical collecting
duct (Ecelbarger et al., 2001), and this may synergize with aldosterone
to enhance Na + reabsorption during hypovolemia.
Pharmacological Modification of the Antidiuretic Response
to Vasopressin. Nonsteroidal anti-inflammatory drugs
(NSAIDs), particularly indomethacin, enhance the
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CHAPTER 25
REGULATION OF RENAL FUNCTION AND VASCULAR VOLUME