Role of the adenosine(2A) receptor-epoxyeicosatrienoic acid pathway in the development of salt-sensitive hypertension.
Activation of rat adenosine(2A) receptors (A(2A) R) dilates preglomerular microvessels, an effect mediated by epoxyeicosatrienoic acids (EETs). High salt (HS) intake increases epoxygenase activity and adenosine levels. A greater vasodilator response to a stable adenosine analog, 2-chloroadenosine (2-CA), was seen in kidneys obtained from HS-fed rats which was mediated by increased EET release. Because this pathway is antipressor, we examined the role of the A(2A) R-EET pathway in a genetic model of salt-sensitive hypertension, the Dahl salt-sensitive (SS) rats. Dahl salt resistant (SR) rats fed a HS diet demonstrated a greater renal vasodilator response to 2-CA. In contrast, Dahl SS rats did not exhibit a difference in the vasodilator response to 2-CA whether fed normal salt (NS) or HS diet. In Dahl SR but not Dahl SS rats, HS intake significantly increased purine flux, augmented the protein expression of A(2A) R and cytochrome P450 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. In vivo inhibition of the A(2A) R-EET pathway in Dahl SR rats fed a HS diet results in reduced renal EETs levels, diminished natriuretic capacity and hypertension, thus supporting a role for the A(2A) R-EET pathway in the adaptive natriuretic response to modulate blood pressure during salt loading. An 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.
Department of Pharmacology, New York Medical College, Valhalla, NY, USA. mairead carroll@nymc.edu
Mairéad A
MA
Carroll
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000378:metabolism* / Q000473:pathology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*
D015777:Eicosanoids; D043705:Receptor, Adenosine A2A; D017673:Sodium Chloride, Dietary; D016718:Arachidonic Acid