Affiliation:
1. From the Department of Physiology (P.M.O., M.L., A.W.C.), Medical College of Wisconsin, Milwaukee; and the Department of Physiology and Pathophysiology (L.L.), Shanghai Medical College, Fudan University, Shanghai, China.
Abstract
It has been reported previously that H
+
efflux via the Na
+
/H
+
exchange stimulates NAD(P)H oxidase-dependent superoxide (O
2
·−
) production in medullary thick ascending limb. We have demonstrated recently that
N
-methyl-amiloride-sensitive O
2
·−
production is enhanced in the thick ascending limb of Dahl salt-sensitive (SS) rats, suggesting that H
+
efflux through Na
+
/H
+
exchangers may promote renal oxidative stress and the development of hypertension in these animals. In the current study we demonstrate, using selective and potent inhibitors, that inhibition of Na
+
/H
+
exchange does not mediate the ability of
N
-methyl-amiloride to inhibit thick ascending limb O
2
·−
production. To determine the mechanism of action of
N
-methyl-amiloride, we examined H
+
efflux and O
2
·−
production in SS and SS.13
BN
thick ascending limbs of prehypertensive, 0.4% NaCl-fed rats. Tissue strips containing the medullary thick ascending limb were isolated from male SS and salt-resistant consomic SS.13
BN
rats, loaded with either dihydroethedium or 2′,7′-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl ester, and imaged in a heated tissue bath. In Na
+
-replete media, activation of Na
+
/H
+
exchange using an NH
4
Cl prepulse did not stimulate thick ascending limb O
2
·−
production. In Na
+
-free media containing BaCl
2
in which Na
+
/H
+
activity was inhibited, an NH
4
Cl prepulse stimulated O
2
·−
production in medullary thick ascending limb renal tubular segments. This response was enhanced in medullary thick ascending limb of SS rats (slope Δethidium/Δdihydroethedium=0.029±0.004) compared with SS.13
BN
rats (slope=0.010±0.004;
P
<0.04) and could be inhibited by
N
-methyl-amiloride (slope=0.005±0.002 and 0.006±0.002 for SS and SS.13
BN
, respectively). We concluded that only H
+
efflux through a specific, as-yet-unidentified, amiloride-sensitive H
+
channel promotes O
2
·−
production in the medullary thick ascending limb and that this channel is upregulated in SS rats.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Cited by
17 articles.
订阅此论文施引文献
订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献