High-salt diet enhances mouse aortic relaxation through adenosine A 2A receptor via CYP epoxygenases

Mohammed A. Nayeem, Dovenia S. Ponnoth, Matthew A. Boegehold, Darryl C. Zeldin, J R Falck, S. Jamal Mustafa

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


We hypothesize that A2A adenosine receptors (A2A AR) promote aortic relaxation in mice through cytochrome P450 (CYP)-epoxygenases and help to avoid salt sensitivity. Aortas from male mice maintained on a high-salt (HS; 7% NaCl) or normal-salt (NS; 0.45% NaCl) diet for 4-5 wks were used. Concentration-response curves (10-11-10-5 M) for 5′-N-ethylcarboxamidoadenosine (NECA; a nonselective adenosine analog) and CGS 21680 (A2A AR agonist) were obtained with different antagonists including ZM 241385 (A2A AR antagonist; 10-6 M), SCH 58261 (A2A AR antagonist; 10-6 M), Nω-nitro-L- arginine methyl ester (L-NAME; endothelial nitric oxide synthase inhibitor; 10-4 M) and inhibitors including methylsulfonyl- propargyloxyphenylhexanamide (MS-PPOH; CYP epoxygenases inhibitor; 10 -5M), 14,15-epoxyeicosa-5(z)-enoic acid (14,15-EEZE; EET antagonist; 10-5M), dibromo-dodecenyl-methylsulfimide (DDMS; CYP4A inhibitor; 10-5M), and HET0016 (20-HETE inhibitor; 10-5M). At 10 -7 M of NECA, significant relaxation in HS (+22.58 ± 3.12%) was observed compared with contraction in NS (-10.62 ± 6.27%, P < 0.05). ZM 241385 changed the NECA response to contraction (P < 0.05) in HS. At 10-7 M of CGS 21680, significant relaxation in HS (+32.04 ± 3.08%) was observed compared with NS (+10.45 ± 1.34%, P < 0.05). SCH 58261, L-NAME, MS-PPOH, and 14,15-EEZE changed the CGS 21680-induced relaxation to contraction (P < 0.05) in HS. Interestingly, DDMS and HET0016 changed CGS 21680 response to relaxation (P < 0.05) in NS; however, there was no significant difference found between DDMS, HET0016-treated HS and NS vs. nontreated HS group (P > 0.05). CYP2C29 protein was 55% and 74% upregulated in HS vs. NS (P < 0.05) mice aorta and kidney, respectively. CYP4A protein was 30.30% and 35.70% upregulated in NS vs. HS (P < 0.05) mice aorta and kidneys, respectively. A1 AR was downregulated, whereas A 2A AR was upregulated in HS compared with NS. These data suggest that HS may activate CYP2C29 via A2A AR, causing relaxation, whereas NS may contribute to the upregulation of CYP4A causing contraction.

Original languageEnglish (US)
Pages (from-to)R567-R574
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Issue number3
StatePublished - Mar 2009


  • Vasoconstriction
  • Vasodilation

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)


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