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

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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−/−.

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Abbreviations

EDRF:

Endothelium-derived relaxing factors

EDHF:

Endothelium-derived hyperpolarizing factor

L-NAME:

NG-nitro-l-arginine methyl ester

sEH:

Soluble epoxide hydrolase

eNOS:

Endothelial nitric oxide synthase

EET:

Eicosatrienoic acid

NECA:

5′-N-ethylcarboxamidoadenosine

MS-PPOH:

Methylsulfonyl-propargyloxyphenylhexanamide

AUDA:

12-(3-adamantan-1-yl-ureido)dodecanoic acid

DDMS:

Dibromo-dodecenyl-methylsulfimide

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Acknowledgments

The authors would like to thank Dr. Mustafa for his support (HL 027339 and MAN is Co-Investigator in HL 094447), AHA 2250298 (MAB), GM 31278 (JRF), and the Intramural Research Program of the NIEHS/NIH-Z01 ES025034 (DCZ).

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, Center for Cardiovascular and Respiratory Sciences, West Virginia University, 3051 Robert C. Byrd Health Science Center-North, 1 Medical Center Drive, P. O. Box 9229, Morgantown, WV, 26506, USA

    Mohammed A. Nayeem & Matthew A. Boegehold

  2. Division of Intramural Research, NIEHS/NIH, RTP, Durham, NC, 27709, USA

    Darryl C. Zeldin

  3. Department of Biochemistry, UTSWMC, Dallas, TX, 75390, USA

    John R. Falck

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  1. Mohammed A. Nayeem
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  2. Darryl C. Zeldin
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Correspondence to Mohammed A. Nayeem.

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Nayeem, M.A., Zeldin, D.C., Boegehold, M.A. et al. Salt modulates vascular response through adenosine A2A receptor in eNOS-null mice: role of CYP450 epoxygenase and soluble epoxide hydrolase. Mol Cell Biochem 350, 101–111 (2011). https://doi.org/10.1007/s11010-010-0686-0

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