Failure to upregulate the adenosine2A receptor-epoxyeicosatrienoic acid pathway contributes to the development of hypertension in Dahl salt-sensitive rats

1 Department of Pharmacology, New York Medical College, Valhalla, New York; and 2 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas Submitted 21 August 2008 ; accepted in final form 24 September 2008 Adenosine-activated renovascular dilatation in Sprague-Dawley (SD) rats is mediated by stimulating adenosine 2A receptors (A 2A R), which is linked to epoxyeicosatrienoic acid (EET) synthesis. The A 2A R-EET pathway is upregulated by high salt (HS) intake in normotensive SD rats. Because this pathway is antipressor, we examined the role of the A 2A R-EET pathway in Dahl salt-sensitive (SS) rats. Male Dahl salt-resistant (SR) and SS rats were fed either HS (8.0% NaCl) or normal salt (NS; 0.4% NaCl) diet for 7 days. On day 8 , isolated kidneys were perfused with Krebs-Henseleit buffer containing indomethacin and N G -nitro- L -arginine methyl ester and preconstricted with phenylephrine. Bolus injections of the stable adenosine analog 2-chloroadenosine (2-CA; 0.1–20 µg) elicited dose-dependent dilation in both Dahl SR and SS rats. Dahl SR rats fed a HS diet demonstrated a greater renal vasodilator response to 10 µg of 2-CA, as measured by the reduction in renal perfusion pressure, than that of Dahl SR rats fed a NS diet (–104 ± 6 vs. –77 ± 7 mmHg, respectively; P < 0.05). In contrast, Dahl SS rats did not exhibit a difference in the vasodilator response to 2-CA whether fed NS or HS diet (96 ± 6 vs. 104 ± 13 mmHg in NS- and HS-fed rats, respectively). In Dahl SR but not Dahl SS rats, HS intake significantly increased purine flux, augmented the protein expression of A 2A R and the cytochrome P -450 2C23 and 2C11 epoxygenases, and elevated the renal efflux of EETs. Thus the Dahl SR rat is able to respond to HS intake by recruiting EET formation, whereas the Dahl SS rat appears to have exhausted its ability to increase EET synthesis above the levels observed on NS intake, and this inability of Dahl SS rats to upregulate the A 2A R-EET pathway in response to salt loading may contribute to the development of salt-sensitive hypertension. epoxyeicosatrienoic acids; kidney; salt-sensitive hypertension Address for reprint requests and other correspondence: M. A. Carroll, Dept. of Pharmacology, New York Medical College, Valhalla, NY 10595 (e-mail: mairead_carroll{at}nymc.edu )