(Hypertension. 2001;37:467.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
NO Inhibits NaCl Absorption by Rat Thick Ascending Limb Through Activation of cGMP-Stimulated Phosphodiesterase
From the Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, Mich.
Correspondence to Jeffrey L. Garvin, PhD, Division of Hypertension and Vascular Research, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202. E-mail jgarvin1{at}hfhs.org
In the isolated, perfused rat thick ascending limb (THAL), L-arginine (L-Arg) stimulates endogenous nitric oxide (NO) production, which inhibits NaCl absorption. However, the intracellular cascade responsible for the effects of NO has not been studied. We hypothesized that endogenous NO inhibits THAL NaCl transport by increasing cGMP, which activates protein kinase G (PKG) and cGMP-stimulated phosphodiesterase (PDE II), which, in turn, decreases cAMP levels. THALs from rats were isolated and perfused, and net chloride flux (JCl-) was measured. L-Arg was used to stimulate NO production. Adding L-Arg (0.5 mmol/L) to the bath decreased JCl- from 154.4±9.9 to 101.9±14.1 pmol · mm-1 · min-1, a 35.2% decrease (n=6; P<0.05). In the presence of the soluble guanylate cyclase inhibitor LY-83583 (10 µmol/L), adding L-Arg to the bath did not affect THAL JCl- (143.7±28.1 versus 136.7±22.2 pmol · mm-1 · min-1; n=6). LY-83583 alone had no effect on JCl-. In the presence of the PDE II inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) 50 µmol/L, L-Arg reduced JCl- by only 13% (142.1±8.9 versus 122.7±11.5 pmol · mm-1 · min-1; P<0.05; n=6). EHNA alone had no effect on THAL JCl-. In the presence of 10-5 mol/L dibutyryl (db)-cAMP, L-Arg did not significantly reduce JCl- (116.3±18.2 versus 102.6±15.6 pmol · mm-1 · min-1; n=6). db-cAMP (10-5 mol/L) had no effect on THAL JCl-. In the presence of the PKG inhibitor KT-5823 (2 µmol/L), L-Arg lowered JCl- from 142.6±14.1 to 85.9±8.3 pmol · mm-1 · min-1, a decrease of 35.6% (n=8; P<0.05). We conclude that (1) endogenous NO inhibits THAL JCl- by stimulating soluble guanylate cyclase and increasing cGMP; (2) NO inhibits THAL JCl- by stimulation of PDE II, which, in turn, decreases cAMP levels; and (3) PKG does not mediate NO-induced inhibition of THAL JCl-.
Key Words: limb, thick, ascending • nitric oxide • cGMP • phosphodiesterases • transport, chloride
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