Inhibition of the Adenosine _2A Receptor-Epoxyeicosatrienoic Acid Pathway Renders Dahl Salt-Resistant Rats Hypertensive

Abstract

Abstract-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 108Ϯ2 mm Hg to 136Ϯ5 mm Hg and 140Ϯ4 mm Hg when treated with MS-PPOH or ZM, respectively (PϽ0.001). Plasma levels of EETs and dihydroxyeicosatrienoic acids during salt loading and MS-PPOH (29.3Ϯ1.8 ng/mL) or ZM treatment (9.8Ϯ0.5 ng/mL) did not increase to the same extent as in vehicle-treated rats (59.4Ϯ1.7 ng/mL; PϽ0.001), and renal levels of EETsϩdihydroxyeicosatrienoic 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 ϩ balance, and plasma Na ϩ levels were significantly increased (163.3Ϯ1.2 and 158.1Ϯ4.5 mEq/L, respectively) compared with vehicle-treated rats (142.1Ϯ1 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.

Role of CYP2C9 genetic variants for salt sensitivity and the regulation of the renin–angiotensin–aldosterone system in normotensive men

“…#, P < 0.05 compared with low salt within group. Although the inability to upregulate renal CYP2C activity and EET synthesis has been linked to salt-sensitive hypertension in rats [2,[6][7][8][9], salt-sensitive BP regulation was not associated with either CYP2C9 Ã 2 or CYP2C9 Ã 3 genetic variants in our cohort of normotensive young men. In this regard, it is important to note that power calculations [22] revealed that our study had a power of 0.998 to detect a 3 mmHg difference in the response of MAP to dietary salt intake (DMAP) between CYP2C9 Ã 1/ Ã 1 individuals and CYP2C9 Ã 2 allele carriers, and a power of 0.895 to detect a 3 mmHg difference between CYP2C9 Ã 1/ Ã 1 individuals and CYP2C9 Ã 3 allele carriers.…”

“…However, it is tempting to speculate that in saltsensitive individuals carrying the CYP2C9 Ã 3 allele the effect of blunted EET synthesis leads to a more pronounced dysfunction in renal sodium handling than in salt-resistant men. Recently, an inability of Dahl saltsensitive rats to stimulate adenosine 2A receptors and to augment EET synthesis in response to salt loading was suggested to contribute to the development of salt-sensitive hypertension [9,34].…”

“…These findings are accompanied by and possibly attributable to an upregulation of renal CYP2C23 content and increase in activity [2,5], suggesting an adaptive response of renal EET formation to excess dietary salt. Moreover, inability to upregulate renal CYP2C activity has been linked to salt-sensitive hypertension in rats [2,[6][7][8][9].…”

Midkine Regulates BP through Cytochrome P450–Derived Eicosanoids

“…The vasodilation and BP-lowering effect of adenosine are induced by A 2A R, 25 whose effects are mediated via stimulation of EET synthesis. 26 We asked whether MK directly regulated the expression of the adenosine A 2A R in renal endothelial cells. Quantitative RT-PCR revealed that the mRNA expression of the adenosine A 2A R was not affected by MK (data not shown).…”

“…26 Activation of the A 2A R stimulates EET synthesis, and contributes to vasodilation. 25,26 Because the A 2A R antagonist ZM241385 induced a striking elevation of BP in Mdk 2/2 but not Mdk +/+ mice (Figure 5D), we concluded that MK is required to mediate the effect of A 2A R, likely through the generation of EETs.…”