Cell Physiology of Diuretics
Overview
diuresis:
increased discharge of urine
water diuresis:
sustained low permeability of collect duct due to inhibition of ADH release
osmotic diuresis:
high secretion/low reabsorption of osmotically active substances
examples: diabetic glucose diuresis, mannitol diuresis
saluretics: increase discharge of salt
diuretics: inhibit salt reabsorption
functional segments of the nephron responsible for renal sodium reabsorption
proximal tubule: isotonic absorption (67%)
Loop of Henle: countercurrent multiplier (20%)
early distal tubule: diluting segment (10-50%)
late distal tubule/collecting duct: scavenging Na
+
reabs (5-30%)
15-80% makes it to end without being reabsorbed
macula densa: senses how much salt is delivered to distal tubule
development of nephron segments
saltwater invertebrates have only PCT; freshwater fish add DCT, amphibians add collecting duct, mammals add Loop of Henle
versatility of salt reabsorption is therefore an evolutionary advantage
Diuretic and Saluretic Effects
4 diuretics (
acetazolamide, furosemide, chlorothiazide, amiloride
)
originally antibacterial agents, but also affect Na
+
-absorbing function of different parts of nephron
all sections of the nephron use the basolateral Na
+
/K
+
pump to secondarily drive transport
proximal tubule
carbonic anhydrase converts CO
2
to HCO
3
-
inside cell and produces CO
2
from HCO
3
-
outside
this produces high [H
+
], which drives apical Na
+
/H
+
antiporter (NHE-3) to absorb Na
+
from lumen
Na
+
is then cotransported with HCO
3
-
through basolateral by NBC (sodium bicarbonate channels)
acetazolamide
inhibits intracellular and extracellular carbonic anhydrase
lowered [HCO
3
-
] blocks NBC preventing sodium to decrease intracellularly
also, since NHE-3 is secondarily blocked, intracellular pH rises
this produces bicarbonaturia (HCO
3
-
in urine and weak diuresis)
thick ascending loop of Henle
apical NKCC (Na
+
/K
+
/2Cl
-
) channels cotransport these ions using Na
+
gradient
K
+
leaves through apical channels, Cl through basolateral this depolarizes the membrane to -40 mV
paracellular space highly permeable to cations here, so K
+
and Na
+
migrate to maintain electroneutrality
lumen +30mV
furosemide
blocks NKCC, so no sodium transport (also no lumenal potential built up)
strong diuresis (efficient: 6 Na
+
absorbed per ATP)
HOWEVER K
+
still leaves through apical channels, producing kaluresis, hypokalemia (heart problems)
produces saluresis, kaluresis, calciuria, and alkalosis
early distal tubule
apical NCC (Na
+
and Cl
-
) cotransport these ions, KCl flows out through basolat.channels
chlorothiazide
blocks NCC
produces diuresis, saluresis, kaliuresis, hypocaliuria
late distal tubule
apical ENaC (epith sodium channel)just absorb Na
+
other intercalating cells are present in the late distal tubule that neutralize the charge
apical H
+
ATPase secretes H
+
carb.anh. replaces it with Cl
-
/HCO
3
-
(in/out) antiporters and Cl
-
channels (out)
amiloride
blocks ENaC
produces moderate natriuresis as well as antikaliuresis
collecting duct
ENaC channels, also K
+
(out) and Cl
-
(in) channels, producing negative lumen (50mV)
amiloride
blocks ENaC, so lumen no longer negative
also stops K
+
secretion, so produces antikaliuresis in addition to moderate natriuresis
Efficiency of Each
one ATP transports 4.5 NaHCO
3
in PT, 6 NaCl in Loop, 3 NaCl in EDT, 3 Na+ in CD
lower ratio means moving against larger concentration gradient, BUT also weaker diuresis when inhibited
Modulation of Response
well-equipped to adapt to low Na
+
diets
making more Na
+
channels, more ATPases, and more ATP
sensor for Na
+
depletion: mineralcorticoids (aldosterone) activate transcription factors