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

676 7. As water and solutes accumulate in the intercellular space, hydrostatic
pressure increases, thus providing a driving force for bulk
water flow. Bulk water flow carries solute (solute convection) out
of the intercellular space into the interstitial space and, finally,
into the peritubular capillaries. The movement of fluid into peritubular
capillaries is governed by the same Starling forces that
determine transcapillary fluid movement for any capillary bed.
A Luminal space Epithelial cell Peritubular space
K +
1 ATPase
Na +
Na +
K + K +
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Mechanism of Organic Acid and Organic Base Secretion. The kidney
is a major organ involved in the elimination of organic chemicals
from the body. Organic molecules may enter the renal tubules
by glomerular filtration of molecules not bound to plasma proteins
or may be actively secreted directly into tubules. The proximal
tubule has a highly efficient transport system for organic acids and
an equally efficient but separate transport system for organic
bases. Current models for these secretory systems are illustrated
in Figure 25–4. Both systems are powered by the sodium pump in
the basolateral membrane, involve secondary and tertiary active
transport, and use a facilitated-diffusion step. There are at least nine
different organic acid and five different organic base transporters;
the precise roles that these transporters play in organic acid and base
transport remain ill defined (Dresser et al., 2001). A family of
organic anion transporters (OATs) countertransport organic anions
with dicarboxylates (Figure 25–4A). OATs most likely exist as α-
helical dodecaspans connected by short segments of ~10 or fewer
amino acids, except for large interconnecting stretches of amino
acids between helices 1 and 2 and helices 6 and 7 (Eraly et al.,
2004); see Chapter 5.
Renal Handling of Specific Anions and Cations. Reabsorption of
Cl – generally follows reabsorption of Na + . In segments of the tubule
with low-resistance tight junctions (i.e., “leaky” epithelium), such
as the proximal tubule and thick ascending limb, Cl – movement can
occur paracellularly. With regard to transcellular Cl – flux, Cl – crosses
the luminal membrane by antiport with formate and oxalate (proximal
tubule), symport with Na + /K + (thick ascending limb), symport
with Na + (DCT), and antiport with HCO 3–
(collecting-duct system).
Cl – crosses the basolateral membrane by symport with K + (proximal
tubule and thick ascending limb), antiport with Na + /HCO 3–
(proximal
tubule), and Cl – channels (thick ascending limb, DCT, collecting-duct
system).
Eighty to ninety percent of filtered K + is reabsorbed in the
proximal tubule (diffusion and solvent drag) and thick ascending
limb (diffusion) largely through the paracellular pathway. In contrast,
the DCT and collecting-duct system secrete variable amounts
of K + by a conductive (channel-mediated) pathway. Modulation of
the rate of K + secretion in the collecting-duct system, particularly
by aldosterone, allows urinary K + excretion to be matched with
dietary intake. The transepithelial potential difference (V T
), lumenpositive
in the thick ascending limb and lumen-negative in the collecting-duct
system, provides an important driving force for K +
reabsorption and secretion, respectively.
Most of the filtered Ca 2+ (~70%) is reabsorbed by the proximal
tubule by passive diffusion through a paracellular route. Another
25% of filtered Ca 2+ is reabsorbed by the thick ascending limb in
part by a paracellular route driven by the lumen-positive V T
and in
part by active transcellular Ca 2+ reabsorption modulated by parathyroid
hormone (PTH; see Chapter 44). Most of the remaining Ca 2+ is
Facilitated
diffusion
Symporter
Antiporter
A -
B Luminal space Epithelial cell Peritubular space
K +
1 ATPase
Na +
Antiporter
LM
2
LM
reabsorbed in DCT by a transcellular pathway. The transcellular
pathway in the thick ascending limb and DCT involves passive Ca 2+
influx across the luminal membrane through Ca 2+ channels
(TRPV5), followed by Ca 2+ extrusion across the basolateral membrane
by a Ca 2+ -ATPase. Also, in DCT and CNT, Ca 2+ crosses the
basolateral membrane by Na + -Ca 2+ exchanger (antiport).
Inorganic phosphate (P i
) is largely reabsorbed (80% of filtered
load) by the proximal tubule. The Na + -P i
symporter uses the
free energy of the Na + electrochemical gradient to transport P i
into
2
αKG 2 - αKG 2-
A -
Na +
3
BL
H + H +
Antiporter 3
C + C +
BL
Na +
Facilitated
diffusion
Figure 25–4. Mechanisms of organic acid (A) and organic base
(B) secretion in the proximal tubule. The numbers 1, 2, and 3
refer to primary, secondary, and tertiary active transport. A – ,
organic acid [anion]; C + , organic base [cation]; αKG 2– , α-ketoglutarate
but also other dicarboxylates. BL and LM indicate basolateral
and luminal membranes, respectively.