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Inhibition of Na-K-ATPase in thick ascending limbs by NO depends on O₂^– and is diminished by a high-salt diet

¹Division of Nephrology and ²Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, Michigan 48202

Submitted 4 December 2003 ; accepted in final form 22 April 2004

A high-salt diet enhances nitric oxide (NO)-induced inhibition of transport in the thick ascending limb (THAL). Long exposures to NO inhibit Na-K-ATPase in cultured cells. We hypothesized that NO inhibits THAL Na-K-ATPase after long exposures and a high-salt diet would augment this effect. Rats drank either tap water or 1% NaCl for 7–10 days. Na-K-ATPase activity was assessed by measuring ouabain-sensitive ATP hydrolysis by THAL suspensions. After 2 h, spermine NONOate (SPM; 5 µM) reduced Na-K-ATPase activity from 0.44 ± 0.03 to 0.30 ± 0.04 nmol P_i·µg protein^–1·min^–1 in THALs from rats on a normal diet (P < 0.03). Nitroglycerin also reduced Na-K-ATPase activity (P < 0.04). After 20 min, SPM had no effect (change –0.07 ± 0.05 nmol P_i·µg protein^–1·min^–1). When rats were fed high salt, SPM did not inhibit Na-K-ATPase after 120 min. To investigate whether ONOO^– formed by NO reacting with O₂^– was involved, we measured O₂^– production. THALs from rats on normal and high salt produced 35.8 ± 0.3 and 23.7 ± 0.8 nmol O₂^–·min^–1·mg protein^–1, respectively (P < 0.01). Because O₂^– production differed, we studied the effects of the O₂^– scavenger tempol. In the presence of 50 µM tempol, SPM did not inhibit Na-K-ATPase after 120 min (0.50 ± 0.05 vs. 0.52 ± 0.07 nmol P_i·µg protein^–1·min^–1). Propyl gallate, another O₂^– scavenger, also prevented SPM-induced inhibition of Na-K-ATPase activity. SPM inhibited pump activity in tubules from rats on high salt when O₂^– levels were increased with xanthine oxidase and hypoxanthine. We concluded that NO inhibits Na-K-ATPase after long exposures when rats are on a normal diet and this inhibition depends on O₂^–. NO donors do not inhibit Na-K-ATPase in THALs from rats on high salt due to decreased O₂^– production.

superoxide; nitric oxide; Na transport; hypertension

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