Inhibition of the Adenosine2A Receptor-Epoxyeicosatrienoic Acid Pathway Renders Dahl Salt-Resistant Rats Hypertensive

Adenosine-induced renovasodilation in Dahl rats is mediated via activation of adenosine(2A) receptors (A(2A)Rs) and stimulation of epoxyeicosatrienoic acid (EET) synthesis. Unlike Dahl salt-resistant rats, salt-sensitive rats exhibit an inability to upregulate the A(2A)R-EET pathway with salt loading; therefore, we examined the effect of in vivo inhibition of the A(2A)R-EET pathway on blood pressure and the natriuretic response to salt-loading in Dahl salt-resistant rats. N-Methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH; 20 mg/kg per day), an epoxygenase inhibitor, or ZM241385 (ZM; 5 mg/kg per day), an A(2A)R antagonist, was given daily as an IV bolus dose for 3 days before and after placing rats on high salt intake (2% saline). After 3 days of high salt, systolic blood pressure per 24 hours increased from 108 +/- 2 mm Hg to 136 +/- 5 mm Hg and 140 +/- 4 mm Hg when treated with MS-PPOH or ZM, respectively (P < 0.001). Plasma levels of EETs and dihydroxyeicosatrienoic acids during salt loading and MS-PPOH (29.3 +/- 1.8 ng/mL) or ZM treatment (9.8 +/- 0.5 ng/mL) did not increase to the same extent as in vehicle-treated rats (59.4 +/- 1.7 ng/mL; P < 0.001), and renal levels of EETs + dihydroxyeicosatrienoic acids were 2-fold lower with MS-PPOH or ZM treatment. On day 3 of the high salt intake, MS-PPOH- and ZM-treated rats exhibited a positive Na+ balance, and plasma Na+ levels were significantly increased (163.3 +/- 1.2 and 158.1 +/- 4.5 mEq/L, respectively) compared with vehicle-treated rats (142.1 +/- 1 mEq/L), reflecting a diminished natriuretic capacity. These data support a role for the A(2A)R-EET pathway in the adaptive natriuretic response to modulate blood pressure during salt loading. (Hypertension. 2009; 54: 1284-1290.)