Inhibition of the adenosine2A receptor-epoxyeicosatrienoic acid pathway renders dahl salt-resistant rats hypertensive

Elvira L. Liclican, Anabel B. Doumad, Jianjin Wang, Jing Li, John R. Falck, Charles T. Stier, Mairéad A. Carroll

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Adenosine-induced renovasodilation in Dahl rats is mediated via activation of adenosine2A receptors (A2ARs) and stimulation of epoxyeicosatrienoic acid (EET) synthesis. Unlike Dahl salt-resistant rats, salt-sensitive rats exhibit an inability to upregulate the A2AR-EET pathway with salt loading; therefore, we examined the effect of in vivo inhibition of the A2AR-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 A2AR 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 A2AR-EET pathway in the adaptive natriuretic response to modulate blood pressure during salt loading.

Original languageEnglish (US)
Pages (from-to)1284-1290
Number of pages7
JournalHypertension
Volume54
Issue number6
DOIs
StatePublished - Dec 1 2009

Keywords

  • Adenosine
  • EETs
  • Salt-sensitive hypertension

ASJC Scopus subject areas

  • Internal Medicine

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