Page 271 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 15 Diuretic Agents 257

Thick Distal
ascending convoluted
Lumen- limb Interstitium- Lumen- tubule Interstitium-
urine blood urine blood
NKCC2 NCC
Na + Na + Na + Na +
K + ATP ATP
2Cl – K + Cl – K +

K + + R PTH
(+) Potential K +
Cl – Ca 2+
Ca 2+
2 +
Mg , Ca 2 +
Na +
Ca 2+
FIGURE 15–3 Ion transport pathways across the luminal and
basolateral membranes of the thick ascending limb cell. The lumen ATP
+
positive electrical potential created by K back diffusion drives divalent H +
(and monovalent) cation reabsorption via the paracellular pathway.
NKCC2 is the primary transporter in the luminal membrane.

FIGURE 15–4 Ion transport pathways across the luminal and
have aquaretic activity. The thin ascending limb is relatively water- basolateral membranes of the distal convoluted tubule cell. As in all
+
+
impermeable but is permeable to some solutes. tubular cells, Na /K -ATPase is present in the basolateral membrane.
The thick ascending limb (TAL), which follows the thin limb NCC is the primary sodium and chloride transporter in the luminal
of Henle’s loop, actively reabsorbs NaCl from the lumen (about membrane. R, parathyroid hormone (PTH) receptor.
25% of the filtered sodium), but unlike the proximal tubule and
the thin descending limb of Henle’s loop, it is nearly impermeable
to water. Salt reabsorption in the TAL therefore dilutes the tubu- transport in the DCT is an electrically neutral thiazide-sensitive
+
−
lar fluid, and for this reason, the TAL is called a diluting segment. Na /Cl cotransporter (NCC; Figure 15–4).
+
Medullary portions of the TAL contribute to medullary hyperto- Because K does not recycle across the apical membrane of the
nicity and thereby also play an important role in concentration of DCT as it does in the TAL, there is no lumen-positive potential in
2+
2+
urine by the collecting duct. this segment, and Ca and Mg are not driven out of the tubular
2+
The NaCl transport system in the luminal membrane of lumen by electrical forces. Instead, Ca is actively reabsorbed by
+
−
+
2+
the TAL is a Na /K /2Cl cotransporter (called NKCC2 or the DCT epithelial cell via an apical Ca channel and basolateral
+
2+
NK2CL) (Figure 15–3). This transporter is selectively blocked Na /Ca exchanger (Figure 15–4). This process is regulated by
by diuretic agents known as “loop” diuretics (discussed later in parathyroid hormone.
−
+
+
chapter). Although the Na /K /2Cl transporter is itself electri-
cally neutral (two cations and two anions are cotransported), the COLLECTING TUBULE SYSTEM
+
action of the transporter contributes to excess K accumulation
+
within the cell. Back diffusion of this K into the tubular lumen The collecting tubule system that connects the DCT to the renal
(via the ROMK channel) causes a lumen-positive electrical pelvis and the ureter consists of several sequential tubular segments:
potential that provides the driving force for reabsorption of cat- the connecting tubule, the collecting tubule, and the collecting
ions—including magnesium and calcium—via the paracellular duct (formed by the connection of two or more collecting tubules).
pathway. Thus, inhibition of salt transport in the TAL by loop Although these tubule segments may be anatomically distinct, the
diuretics, which reduces the lumen-positive potential, causes an physiologic gradations are more gradual, and in terms of diuretic
increase in urinary excretion of divalent cations in addition to activity it is easier to think of this complex as a single segment of
NaCl. the nephron containing several distinct cell types. The collecting
tubule system is responsible for only 2–5% of NaCl reabsorption
DISTAL CONVOLUTED TUBULE by the kidney. Despite this small contribution, it plays an impor-
tant role in renal physiology and in diuretic action. As the final site
Only about 10% of the filtered NaCl is reabsorbed in the distal of NaCl reabsorption, the collecting system is responsible for tight
+
convoluted tubule (DCT). Like the TAL of Henle’s loop, this regulation of body fluid volume and for determining the final Na
segment is relatively impermeable to water, and NaCl reabsorp- concentration of the urine. Furthermore, the collecting system is
tion further dilutes the tubular fluid. The mechanism of NaCl the site at which mineralocorticoids exert a significant influence.