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

High salt (4% NaCl, HS) diet modulates adenosine-induced vascular response through adenosine A2A receptor (A2AAR). Evidence suggests that A2AAR 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 A2AAR. Therefore, we hypothesized that HS enhances adenosine-induced relaxation through EETs in A2AAR, but exaggerates contraction in A2AAR. Organ bath and Western blot experiments were conducted in HS and normal salt (NS, 0.18% NaCl)-fed A2AAR and A2AAR mice aorta. HS produced concentration-dependent relaxation to non-selective adenosine analog, NECA in A2AAR, whereas contraction was observed in A2AAR mice and this was attenuated by A1AR antagonist (DPCPX). CGS 21680 (selective A2AAR agonist) enhanced relaxation in HS-A2AAR versus NS-A2AAR, which was blocked by EETs antagonist (14,15-EEZE). Compared with NS, HS significantly upregulated the expression of vasodilators A2AAR and cyp2c29, whereas vasoconstrictors A1AR and cyp4a in A2AAR were downregulated. In A2AAR mice, however, HS significantly downregulated the expression of cyp2c29, whereas A1AR and cyp4a were upregulated compared with A2AAR mice. Hence, our data suggest that in A2AAR, HS enhances A2AAR-induced relaxation through increased cyp-expoxygenases-derived EETs and decreased A1AR levels, whereas in A2AAR, HS exaggerates contraction through decreased cyp-epoxygenases and increased A1AR levels.