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Articles in PresS, published online ahead of print August 9, 2001
Am J Physiol Renal Physiol, 10.1152/ajprenal.0075.2001
Submitted on March 8, 2001
Accepted on June 27, 2001
1 Hypertension and Vascular Research, Henry Ford Hospital, Detroit, MI, USA
* To whom correspondence should be addressed. E-mail: pabloortiz33{at}hotmail.com.
We have reported that 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 hypothesize that NO decreases THAL JCl- by inhibiting the Na+/K+/2Cl- cotransporter. THALs from Sprague-Dawley rats were isolated and perfused. Intracellular sodium (Nai) and chloride concentrations (Cli) were measured with sodium green and SPQ, respectively. The NO donor spermine NONOate (SPM) decreased Nai from 13.5±1.2 mM to 9.6±1.6 mM (p<0.05) and also decreased Cli (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 to 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 nmol O2/mg protein/min in SPM-treated tubules and to 125.6 ± 23.4 nmol O2/mg protein/min in furosemide-treated tubules. In the presence of 125 mM extracellular Na+, nystatin increased QO2 by 104 ± 7% in NO-treated tubules and 94 ± 20% in furosemide-treated tubules. We conclude that NO decreases THAL JCl- by inhibiting Na+/K+/2Cl- cotransport, rather than inhibiting apical K+ channels or the sodium pump.
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