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2-Adrenergic-mediated tubular NO production
inhibits thick ascending limb chloride absorption
Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Michigan 48202
Stimulation
of 
2-adrenergic receptors inhibits transport in various
nephron segments, and the thick ascending limb of the loop of Henle
(THAL) expresses 2-receptors. We hypothesized that selective 2-receptor activation decreases NaCl
absorption by cortical THALs through activation of NOS and increased
production of NO. We found that the 2-receptor agonist
clonidine (10 nM) decreased chloride flux
(JCl) from 119.5 ± 15.9 to
67.4 ± 13.8 pmol · mm
1 · min1 (43%
reduction; P < 0.02), whereas removal of clonidine
from the bath increased JCl by 20%. When NOS
activity was inhibited by pretreatment with 5 mM
NG-nitro-L-arginine methyl ester,
the inhibitory effects of clonidine on THAL JCl
were prevented (81.7 ± 10.8 vs. 71.6 ± 6.9 pmol · mm1 · min1).
Similarly, when the NOS substrate L-arginine was deleted
from the bath, addition of clonidine did not decrease THAL
JCl from control (106.9 ± 11.6 vs.
132.2 ± 21.3 pmol · mm1 · min1). When we
blocked the 2-receptors with rauwolscine (1 µM), we found that the inhibitory effect of 10 nM clonidine on THAL
JCl was abolished, verifying that
2, rather than I1, receptors mediate the
effects of clonidine in the THAL. We investigated the mechanism of NOS
activation and found that intracellular calcium concentration did not
increase in response to clonidine, whereas pretreatment with 150 nM
wortmannin abolished the clonidine-mediated inhibition of THAL
JCl, indicating activation of
phosphatidylinositol 3-kinase and the Akt pathway. We found that
pretreatment of THALs with 10 µM LY-83583, an inhibitor of soluble
guanylate cyclase, blocked clonidine-mediated inhibition of THAL
JCl. In conclusion, 2-receptor stimulation decreases THAL JCl by increasing NO
release and stimulating guanylate cyclase. These data suggest that
2-receptors act as physiological regulators of THAL NO
synthesis, thus inhibiting chloride transport and participating in the
natriuretic and diuretic effects of clonidine in vivo.
nitric oxide synthase; clonidine; kidney
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