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Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan 48202
Nitric
oxide (NO) inhibits transport in various nephron segments,
and the thick ascending limb of the loop of Henle (TALH) expresses NO synthase (NOS). However, the effects of NO on
TALH transport have not been extensively studied. We hypothesized that endogenously produced NO directly decreases NaCl transport by the TALH.
We first determined the effect of exogenously added NO on net chloride
flux (JCl). The
NO donor spermine NONOate (SPM; 10 µM) decreased
JCl from 101.2 ± 9.6 to 65.0 ± 7.7 pmol · mm
1 · min1,
a reduction of 35.5 ± 6.4%, whereas controls did not decrease over
time. To determine whether endogenous NO affects cortical TALH
transport, we measured the effect of adding the NOS inhibitor NG-nitro-L-arginine methyl ester
(L-NAME), the substrate
L-arginine (L-Arg), or its enantiomer
D-arginine
(D-Arg) on
JCl.
L-NAME and D-Arg did not alter
JCl; in contrast,
addition of 0.5 mM L-Arg decreased JCl by
40.2 ± 10.4% from control. The inhibition of chloride flux by 0.5 mM L-Arg was abolished by
pretreatment with L-NAME,
indicating that cortical TALH NOS is active, but production of NO is
substrate-limited in our preparation. Furthermore, cortical TALH
chloride flux increased following removal of 0.5 mM
L-Arg from the bath, indicating
that the reductions in chloride flux observed in response to
L-Arg are not the result of
NO-mediated cytotoxicity. We conclude that
1) exogenous NO decreases cortical TALH JCl;
2) cortical TALHs produce NO in the
presence of L-Arg, which
decreases JCl;
and 3) the response of cortical
TALHs to L-Arg is reversible in
vitro. These data suggest an important role for locally produced NO,
which may act via an autocrine mechanism to directly affect TALH sodium
chloride transport. Thus TALH NO synthesis and inhibition of chloride
transport may contribute to the diuretic and natriuretic effects of NO
observed in vivo.
nitric oxide synthase; arginine; kidney; loop of Henle
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