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cotransporter
activity
Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan 48202
First published August 9, 2001;
10.1152/ajprenal.0075.2001.
We have reported that nitric oxide (NO)
inhibits thick ascending limb (THAL) chloride absorption
(JCl
). NaCl transport in the THAL
depends on apical Na+-K+-2Cl
cotransporters, apical K+ channels, and basolateral
Na+-K+-ATPase. However, the transporter
inhibited by NO is unknown. We hypothesized that NO decreases THAL
JCl by inhibiting the
Na+-K+-2Cl cotransporter. THALs
from Sprague-Dawley rats were isolated and perfused. Intracellular
sodium ([Na+]i) and chloride concentrations
([Cl]i) were measured with sodium green and
SPQ, respectively. The NO donor spermine NONOate (SPM) decreased
[Na+]i from 13.5 ± 1.2 to 9.6 ± 1.6 mM (P < 0.05) and also decreased [Cl]i (P < 0.01). We next
tested whether NO decreases
Na+-K+-2Cl cotransporter activity
by measuring the initial rate of Na+ transport. In the
presence of SPM in the bath, initial rates of Na+ entry
were 49.6 ± 6.0% slower compared with control rates
(P < 0.05). To determine whether NO inhibits apical
K+ channel activity, we measured the change in membrane
potential caused by an increase in luminal K+ from 1 to 25 mM using a potential-sensitive fluorescent dye. In the presence of SPM,
increasing luminal K+ concentration depolarized THALs to
the same extent as it did in control tubules. We then tested whether a
change in apical K+ permeability could affect NO-induced
inhibition of THAL JCl. In the
presence of luminal valinomycin, which increases K+
permeability, addition of SPM decreased THAL
JCl by 41.2 ± 10.4%, not
significantly different from the inhibition observed in control
tubules. We finally tested whether NO alters the affinity or maximal
rate of Na+-K+-ATPase by measuring oxygen
consumption rate (QO2) in THAL suspensions in
the presence of nystatin in varying concentrations of Na+.
In the presence of 10.5 mM Na+, nystatin increased
QO2 to 119.1 ± 19.2 and 125.6 ± 23.4 nmol O2 · mg
protein1 · min1 in SPM- and
furosemide-treated tubules, respectively. In the presence of 145 mM
extracellular Na+, nystatin increased
QO2 by 104 ± 7 and 94 ± 20% in NO-
and furosemide-treated tubules, respectively. We concluded that NO
decreases THAL JCl by inhibiting
Na+-K+-2Cl cotransport rather
than inhibiting apical K+ channels or the sodium pump.
nitric oxide; chloride transport; sodium-potassium-2 chloride cotransporter; natriuresis; sodium-potassium-adenosinetriphosphatase
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