title: Exaggerated response to adenosine in kidneys from high salt-fed rats: role of epoxyeicosatrienoic acids.
abstract: Cytochrome P-450 (CYP)-dependent epoxyeicosatrienoic acids (EETs) dilate rat preglomerular microvessels when adenosine(2A) receptors (A(2A)R) 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 microM) and L-NAME (200 microM) and preconstricted to approximately 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 microg) resulted in dose-dependent dilation; at 10 microg, 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 mm(2); P < 0.05), as was EET release (132 +/- 23 vs. 38 +/- 18 ng; P < 0.05). HS treatment increased A(2A)R and CYP2C23 protein expression. A selective epoxygenase inhibitor, MS-PPOH (12 microM), 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.
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, 10595, USA.
authors.forename: Elvira L
authors.initials: EL
authors.lastname: Liclican
authors.forename: John C
authors.initials: JC
authors.lastname: McGiff
authors.forename: Paulina L
authors.initials: PL
authors.lastname: Pedraza
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Ferreri
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Mairead A
authors.initials: MA
authors.lastname: Carroll
mesh_terms: D015762:2-Chloroadenosine / Q000494:pharmacology; D015126:8,11,14-Eicosatrienoic Acid / Q000378:metabolism*; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D000090762:Cytochrome P-450 CYP2J2; D004305:Dose-Response Relationship, Drug; D008401:Gas Chromatography-Mass Spectrometry; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010477:Perfusion; D010627:Phenethylamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects; D012982:Sodium, Dietary / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
chemical_list: C000717351:Cyp2c23 protein, rat; D006893:Hydroxyeicosatetraenoic Acids; D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; D012982:Sodium, Dietary; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D015762:2-Chloroadenosine; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D000090762:Cytochrome P-450 CYP2J2; D015126:8,11,14-Eicosatrienoic Acid; D000241:Adenosine