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Am J Physiol Renal Physiol 297: F1168-F1173, 2009. First published August 26, 2009; doi:10.1152/ajprenal.00325.2009
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ARTICLE-COMMENTARY

Extracellular ATP inhibits transport in medullary thick ascending limbs: role of P2X receptors

Guillermo B. Silva1 and Jeffrey L. Garvin1,2

1Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit; and ; 2Department of Physiology, School of Medicine, Wayne State University, Detroit, Michigan

Submitted June 8, 2009 ; accepted in final form August 21, 2009

Absorption of NaCl by the thick ascending limb (TAL) involves active transport and therefore depends on oxidative phosphorylation. Extracellular ATP has pleiotropic effects, including both stimulation and inhibition of transport and inhibition of oxidative phosphorylation. However, it is unclear whether ATP alters TAL transport and how this occurs. We hypothesized that ATP inhibits TAL Na absorption by reducing Na entry. We measured oxygen consumption in TAL suspensions. ATP reduced oxygen consumption in a concentration-dependent manner. The purinergic (P2) receptor antagonist suramin (300 µM) blocked the effect of ATP on TAL oxygen consumption (147 ± 15 vs. 146 ± 16 nmol O2·min–1·mg protein–1). In contrast, the adenosine receptor antagonist theophylline did not block the effect of ATP on oxygen consumption. When Na-K-2Cl cotransport and Na/H exchange were blocked with furosemide (100 µM) plus dimethyl amiloride (100 µM), ATP did not inhibit TAL oxygen consumption (from 78 ± 13 to 98 ± 5 nmol O2·min–1·mg protein–1). The Na ionophore nystatin (200 U/ml) increased TAL oxygen consumption to a similar extent in both ATP- and vehicle-treated samples (368 ± 41 vs. 397 ± 47 nmol O2·min–1·mg protein–1). The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (3 mM) blocked the ATP effects on TAL oxygen consumption (157 ± 10 vs. 165 ± 15 nmol O2·min–1·mg protein–1). The P2X-selective receptor antagonist NF023 blocked the effect of ATP on oxygen consumption, whereas the P2X-selective agonist β-{gamma}-Me-ATP reduced oxygen consumption in a concentration-dependent manner. We conclude that ATP inhibits Na transport-related oxygen consumption in TALs by reducing Na entry and P2X receptors and nitric oxide mediate this effect.

NKCC2; purinergic signaling; NHE


Address for reprint requests and other correspondence: J. L. Garvin, Div. of Hypertension and Vascular Research, Henry Ford Hospital, 2799 W. Grand Blvd., Detroit, MI 48202 (e-mail: jgarvin1{at}hfhs.org).






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