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1Department of Pharmacology, New York Medical College, Valhalla, New York; and 2Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas
Submitted 24 November 2004 ; accepted in final form 30 March 2005
Cytochrome P-450 (CYP)-dependent epoxyeicosatrienoic acids (EETs) dilate rat preglomerular microvessels when adenosine2A receptors (A2AR) are stimulated. As high salt (HS) intake increases epoxygenase activity and adenosine levels, we hypothesized that renal adenosine responses would be greater in HS-fed rats. Male Sprague-Dawley rats were fed either HS (4.0% NaCl) or normal salt (NS; 0.4% NaCl) diet. On day 8, isolated kidneys were perfused with Krebs' buffer containing indomethacin (10 µM) and L-NAME (200 µM) and preconstricted to 
150 mmHg with infusion of phenylephrine (10–7 M). Renal effluents were extracted for analysis of eicosanoids by gas chromatography-mass spectrometry. Bolus injections of the stable adenosine analog 2-chloroadenosine (2-CA; 0.1–10 µg) resulted in dose-dependent dilation; at 10 µg, perfusion pressure (PP) was lowered to a greater extent in the kidneys of HS rats compared with NS rats (–60 ± 4 vs. –31 ± 8 mmHg; P < 0.05) and the area of response was increased (27 ± 6 vs. 9 ± 4 mm2; P < 0.05), as was EET release (132 ± 23 vs. 38 ± 18 ng; P < 0.05). HS treatment increased A2AR and CYP2C23 protein expression. A selective epoxygenase inhibitor, MS-PPOH (12 µM), significantly reduced the response to 2-CA in HS rats; PP, area of response, and EET release decreased by 40, 70, and 81%, respectively, whereas lesser changes were evident in NS kidneys. Thus the greater vasodilator response to 2-CA seen in kidneys obtained from HS-fed rats was mediated by increased EET release. As EETs are renal vasodilator and natriuretic eicosanoids, interactions between adenosine and EETs may contribute to the adaptive response to HS intake.
adenosine receptors; cytochrome P-450
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