Salt modulates vascular response through adenosine A2A receptor in eNOS-null mice: role of CYP450 epoxygenase and soluble epoxide hydrolase

Abstract

High salt (HS) intake can change the arterial tone in mice, and the nitric oxide (NO) acts as a mediator to some of the receptors mediated vascular response. The main aim of this study was to explore the mechanism behind adenosine-induced vascular response in HS-fed eNOS+/+ and eNOS−/− mice The modulation of vascular response by HS was examined using aortas from mice (eNOS+/+ and eNOS−/−) fed 4% (HS) or 0.45% (NS) NaCl-diet through acetylcholine (ACh), NECA (adenosine-analog), CGS 21680 (A2A AR-agonist), MS-PPOH (CYP epoxygenase-blocker; 10−5 M), AUDA (sEH-blocker; 10−5 M), and DDMS (CYP4A-blocker; 10−5 M). ACh-response was greater in HS-eNOS+/+ (+59.3 ± 6.3%) versus NS-eNOS+/+ (+33.3 ± 8.0%; P < 0.05). However, there was no response in both HS-eNOS−/− and NS-eNOS−/−. NECA-response was greater in HS-eNOS−/− (+37.4 ± 3.2%) versus NS-eNOS−/− (+7.4.0 ± 3.8%; P < 0.05). CGS 21680-response was also greater in HS-eNOS−/− (+45.4 ± 5.2%) versus NS-eNOS−/−(+5.1 ± 5.0%; P < 0.05). In HS-eNOS−/−, the CGS 21680-response was reduced by MS-PPOH (+7.3 ± 3.2%; P < 0.05). In NS-eNOS−/−, the CGS 21680-response was increased by AUDA (+38.2 ± 3.3%; P < 0.05) and DDMS (+30.1 ± 4.1%; P < 0.05). Compared to NS, HS increased CYP2J2 in eNOS+/+ (35%; P < 0.05) and eNOS−/− (61%; P < 0.05), but decreased sEH in eNOS+/+ (74%; P < 0.05) and eNOS−/− (40%; P < 0.05). Similarly, CYP4A decreased in HS-eNOS+/+ (35%; P < 0.05) and HS-eNOS−/− (34%; P < 0.05). These data suggest that NS causes reduced-vasodilation in both eNOS+/+ and eNOS−/− via sEH and CYP4A. However, HS triggers possible A2AAR-induced relaxation through CYP epoxygenase in both eNOS+/+ and eNOS−/−.

Adenosine A2A receptor modulates vascular response in soluble epoxide hydrolase-null mice through CYP-epoxygenases and PPARγ

“…5), suggesting that sEH deletion enhances NECA-induced vascular relaxation. Our data show that NECA-induced vascular response in aortas of sEH Ϫ/Ϫ mice is similar to that from our earlier reports in which we found that high-salt diet-fed WT (C57BL/6J) mice had an enhanced NECA-induced relaxation with upregulation of A 2A AR, CYP2J-epoxygenase and downregulation of sEH, whereas, NECA-induced vascular response in aortas of sEH ϩ/ϩ mice is similar to that found in our earlier reports in which low-salt diet-fed WT (C57BL/6J) mice had an enhanced NECA-induced contraction with downregulation of A 2A AR, CYP2J-epoxygenase and upregulation of sEH (37,38). Therefore, in the present study, we used specific A 2A AR antagonists (ZM-241385 and SCH-58261) to rule out the involvement of other adenosine receptors (A 1 , A 2B , A 3 ).…”

“…Recently, we found that there is a possible link between the upregulation of A 2A AR, CYPepoxygenases, and downregulation of sEH with adenosineinduced relaxation in high-salt diet-fed WT mice (C57BL/6J) and eNOS Ϫ/Ϫ (C57BL/6J background) compared with low-salt diet-fed mice (38,39). Also, we found that there is a possible link between the downregulation of A 2A AR, CYP-epoxygenases and upregulation of sEH with NECA-induced contraction in low-salt diet-fed WT mice and eNOS Ϫ/Ϫ (C57BL/6J background) compared with high-salt diet-fed mice (38,39). The current study shows that in the absence of sEH, there is an increase in aortic A 2A AR, CYP2J5, PPAR␥, and a decrease in A 1 AR, PPAR␣ proteins compared with WT mice.…”

“…Also, the targeted disruption of the sEH gene in male mice lowers systolic blood pressure (51). Recently, we found that there is a possible link between the upregulation of A 2A AR, CYP-epoxygenases, and downregulation of sEH with adenosine-induced relaxation in mouse aorta (38). Also, we found that there is a possible link between the downregulation of A 2A AR, CYP-epoxygenases, and upregulation of sEH with 5=-N-ethylcarboxamidoadenosine (NECA)-induced contraction in mouse aorta (38,39).…”

“…Recently, we found that there is a possible link between the upregulation of A 2A AR, CYP-epoxygenases, and downregulation of sEH with adenosine-induced relaxation in mouse aorta (38). Also, we found that there is a possible link between the downregulation of A 2A AR, CYP-epoxygenases, and upregulation of sEH with 5=-N-ethylcarboxamidoadenosine (NECA)-induced contraction in mouse aorta (38,39). Therefore, we hypothesized that the lack of sEH enhances adenosine-induced vascular relaxation through A 2A AR via CYPepoxygenases and PPAR␥.…”

Adenosine Effects on Renal Function in the Rat: Role of Sodium Intake and Cytochrome P450

“…Stimulation of A2R is known to activate the endothelial and possibly also tubular cytochrome P450 (CYP450)-dependent metabolism of arachidonic acid [7,11,12,13,14,15]. Since the major active metabolites of the CYP450 pathway - epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid - are both vasoactive and transport inhibitory, they are likely to mediate the post-ADO changes in excretion.…”