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J Cardiovasc Pharmacol. 2014 May;63(5):385-94. doi: 10.1097/FJC.0000000000000058.

High salt diet exacerbates vascular contraction in the absence of adenosine A₂A receptor.

Author information

1
*Department of Physiology and Pharmacology/Department of Basic Pharmaceutical Sciences, Center for Cardiovascular and Respiratory Sciences, School of Medicine/School of Pharmacy, West Virginia University, Morgantown, WV; †Division of Intramural Research, Pulmonary Department, NIEHS/NIH, Research Triangle Park, NC; ‡IRIBHN, Universite Libre de Bruxelles, Bruxelles, Belgium; and §Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX.

Abstract

High salt (4% NaCl, HS) diet modulates adenosine-induced vascular response through adenosine A(2A) receptor (A(2A)AR). Evidence suggests that A(2A)AR stimulates cyp450-epoxygenases, leading to epoxyeicosatrienoic acids (EETs) generation. The aim of this study was to understand the vascular reactivity to HS and underlying signaling mechanism in the presence or absence of A(2A)AR. Therefore, we hypothesized that HS enhances adenosine-induced relaxation through EETs in A(2A)AR⁺/⁺, but exaggerates contraction in A(2A)AR⁻/⁻. Organ bath and Western blot experiments were conducted in HS and normal salt (NS, 0.18% NaCl)-fed A(2A)AR⁺/⁺ and A(2A)AR⁻/⁻ mice aorta. HS produced concentration-dependent relaxation to non-selective adenosine analog, NECA in A(2A)AR⁺/⁺, whereas contraction was observed in A(2A)AR⁻/⁻ mice and this was attenuated by A₁AR antagonist (DPCPX). CGS 21680 (selective A(2A)AR agonist) enhanced relaxation in HS-A(2A)AR⁺/⁺ versus NS-A(2A)AR⁺/⁺, which was blocked by EETs antagonist (14,15-EEZE). Compared with NS, HS significantly upregulated the expression of vasodilators A(2A)AR and cyp2c29, whereas vasoconstrictors A₁AR and cyp4a in A(2A)AR⁺/⁺ were downregulated. In A(2A)AR⁻/⁻ mice, however, HS significantly downregulated the expression of cyp2c29, whereas A₁AR and cyp4a were upregulated compared with A(2A)AR⁺/⁺ mice. Hence, our data suggest that in A(2A)AR⁺/⁺, HS enhances A(2A)AR-induced relaxation through increased cyp-expoxygenases-derived EETs and decreased A₁AR levels, whereas in A(2A)AR⁻/⁻, HS exaggerates contraction through decreased cyp-epoxygenases and increased A₁AR levels.

PMID:
24390173
PMCID:
PMC4013230
DOI:
10.1097/FJC.0000000000000058
[Indexed for MEDLINE]
Free PMC Article

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