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

Am J Physiol Regul Integr Comp Physiol. 2013 Jan 1;304(1):R23-32. doi: 10.1152/ajpregu.00213.2012. Epub 2012 Nov 14.

Abstract

The interaction between adenosine and soluble epoxide hydrolase (sEH) in vascular response is not known. Therefore, we hypothesized that lack of sEH in mice enhances adenosine-induced relaxation through A(2A) adenosine receptors (AR) via CYP-epoxygenases and peroxisome proliferator-activated receptor γ (PPARγ). sEH(-/-) showed an increase in A(2A) AR, CYP2J, and PPARγ by 31%, 65%, and 36%, respectively, and a decrease in A(1)AR and PPARα (30% and 27%, respectively) vs. sEH(+/+). 5'-N-ethylcarboxamidoadenosine (NECA, an adenosine receptor agonist), CGS 21680 (A(2A) AR-agonist), and GW 7647 (PPARα-agonist)-induced responses were tested with nitro-l-arginine methyl ester (l-NAME) (NO-inhibitor; 10(-4) M), ZM-241385, SCH-58261 (A(2A) AR-antagonists; 10(-6) M), 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, an epoxyeicosatrienoic acid-antagonist; 10(-5) M), 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA; 10 μM) or trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB, sEH-inhibitors; 10(-5) M), and T0070907 (PPARγ-antagonist; 10(-7) M). In sEH(-/-) mice, ACh response was not different from sEH(+/+) (P > 0.05), and l-NAME blocked ACh-responses in both sEH(-/-) and sEH(+/+) mice (P < 0.05). NECA (10(-6) M)-induced relaxation was higher in sEH(-/-) (+12.94 ± 3.2%) vs. sEH(+/+) mice (-5.35 ± 5.2%); however, it was blocked by ZM-241385 (-22.42 ± 1.9%) and SCH-58261(-30.04 ± 4.2%). CGS-21680 (10(-6) M)-induced relaxation was higher in sEH(-/-) (+37.4 ± 5.4%) vs. sEH(+/+) (+2.14 ± 2.8%). l-NAME (sEH(-/-), +30.28 ± 4.8%, P > 0.05) did not block CGS-21680-induced response, whereas 14,15-EEZE (-7.1 ± 3.7%, P < 0.05) did. Also, AUDA and t-AUCB did not change CGS-21680-induced response in sEH(-/-) (P > 0.05), but reversed in sEH(+/+) (from +2.14 ± 2.8% to +45.33 ± 4.1%, and +63.37 ± 7.2, respectively). PPARα-agonist did not relax as CGS 21680 (-2.48 ± 1.1 vs. +37.4 ± 5.4%) in sEH(-/-), and PPARγ-antagonist blocked (from +37.4 ± 5.4% to +9.40 ± 3.1) CGS 21680-induced relaxation in sEH(-/-). Our data suggest that adenosine-induced relaxation in sEH(-/-) may depend on the upregulation of A(2A) AR, CYP2J, and PPARγ, and the downregulation of A(1) AR and PPARα.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8,11,14-Eicosatrienoic Acid / analogs & derivatives
  • 8,11,14-Eicosatrienoic Acid / pharmacology
  • Adamantane / analogs & derivatives
  • Adamantane / pharmacology
  • Adenosine / analogs & derivatives
  • Adenosine / pharmacology
  • Adenosine A2 Receptor Agonists / pharmacology
  • Adenosine A2 Receptor Antagonists / pharmacology
  • Adenosine-5'-(N-ethylcarboxamide) / pharmacology
  • Animals
  • Benzamides / pharmacology
  • Benzoates / pharmacology
  • Butyrates / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Epoxide Hydrolases / genetics
  • Epoxide Hydrolases / physiology*
  • Female
  • Gene Silencing
  • Lauric Acids / pharmacology
  • Male
  • Mice
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Oxygenases / physiology*
  • PPAR gamma / physiology*
  • Phenethylamines / pharmacology
  • Phenylurea Compounds / pharmacology
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • Receptor, Adenosine A2A / physiology*
  • Triazines / pharmacology
  • Triazoles / pharmacology
  • Urea / analogs & derivatives
  • Urea / pharmacology
  • Vasodilation / drug effects
  • Vasodilation / genetics
  • Vasodilation / physiology
  • Vasodilator Agents / pharmacology

Substances

  • 12-(3-adamantan-1-ylureido)dodecanoic acid
  • 14,15-eicosa-5-enoic acid
  • 4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid
  • 5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine
  • Adenosine A2 Receptor Agonists
  • Adenosine A2 Receptor Antagonists
  • Benzamides
  • Benzoates
  • Butyrates
  • Enzyme Inhibitors
  • GW 7647
  • Lauric Acids
  • PPAR gamma
  • Phenethylamines
  • Phenylurea Compounds
  • Pyridines
  • Pyrimidines
  • Receptor, Adenosine A2A
  • T 0070907
  • Triazines
  • Triazoles
  • Vasodilator Agents
  • ZM 241385
  • 2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
  • Adenosine-5'-(N-ethylcarboxamide)
  • Urea
  • Oxygenases
  • Epoxide Hydrolases
  • 8,11,14-Eicosatrienoic Acid
  • Adenosine
  • Adamantane
  • NG-Nitroarginine Methyl Ester