Epoxyeicosatrienoic acids mediate adenosine-induced vasodilation in rat preglomerular microvessels (PGMV) via A 2A receptors

M. K. Cheng, A. B. Doumad, H. Jiang, J R Falck, J. C. McGiff, M. A. Carroll

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

1. Activation of rat adenosine 2A receptors (A 2A R) dilates preglomerular microvessels (PGMV), an effect mediated by epoxyeicosatrienoic acids (EETs). 2. Incubation of PGMV with a selective A 2A R agonist, 2-p-(2-carboxyethyl) phenethylamino-5′-N- ethylcarboxamidoadenosine (CGS 21680; 100 μM), increased isolated PGMV EET levels to 7.57±1.53 ng mg -1 protein from 1.06±0.22 ng mg -1 protein in controls (P<0.05), without affecting hydroxyeicosatetraenoic acid (HETE) levels (10.8±0.69 vs 11.02±0.74 ng mg -1 protein). 3. CGS 21680-stimulated EETs was abolished by preincubation with an A 2A R antagonist, 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl) phenol (ZM241385) (100 μM). A selective epoxygenase inhibitor, methylsulfonyl-propargyloxyphenylhexanamide (MS-PPOH; 12 μM) prevented CGS 21680-induced increase in EETs, indicating inhibition of de novo synthesis of EETs. 4. In pressurized (80 mmHg) renal arcuate arteries (110-130 μm) preconstricted with phenylephrine (20 nM), superfusion with CGS 21680 (0.01-10 μM) increased the internal diameter (i.d.) concentration-dependently; vasodilation was independent of nitric oxide and cyclooxygenase activity. CGS 21680 (10 μM) increased i.d. by 32±6 μm; vasodilation was prevented by inhibition of EET synthesis with MS-PPOH. 5. Addition of 3nM 5,6-EET, 8,9-EET and 11,12-EET increased i.d. by 53±9, 17±4 and 53±5 μm, respectively, whereas 14,15-EET was inactive. The responses to 5,6-EET were, however, significantly inhibited by indomethacin. 6. We conclude that 11,12-EET is the likely mediator of A 2A R-induced dilation of rat PGMV. Activation of A 2A R coupled to de novo EET stimulation may represent an important mechanism in regulating preglomerular microvascular tone.

Original languageEnglish (US)
Pages (from-to)441-448
Number of pages8
JournalBritish Journal of Pharmacology
Volume141
Issue number3
DOIs
StatePublished - Feb 2004

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Microvessels
Vasodilation
Adenosine
Purinergic P1 Receptors
Acids
Purinergic P1 Receptor Agonists
Purinergic P1 Receptor Antagonists
Hydroxyeicosatetraenoic Acids
Proteins
Phenylephrine
Renal Artery
Prostaglandin-Endoperoxide Synthases
Phenol
Indomethacin
Dilatation
Nitric Oxide
2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide
8,9-epoxyeicosatrienoic acid
11,12-epoxy-5,8,14-eicosatrienoic acid

Keywords

  • A receptors
  • A receptors
  • Adenosine
  • Cytochrome P450
  • Rat renal artery
  • Renal EETs

ASJC Scopus subject areas

  • Pharmacology

Cite this

Epoxyeicosatrienoic acids mediate adenosine-induced vasodilation in rat preglomerular microvessels (PGMV) via A 2A receptors. / Cheng, M. K.; Doumad, A. B.; Jiang, H.; Falck, J R; McGiff, J. C.; Carroll, M. A.

In: British Journal of Pharmacology, Vol. 141, No. 3, 02.2004, p. 441-448.

Research output: Contribution to journalArticle

Cheng, M. K. ; Doumad, A. B. ; Jiang, H. ; Falck, J R ; McGiff, J. C. ; Carroll, M. A. / Epoxyeicosatrienoic acids mediate adenosine-induced vasodilation in rat preglomerular microvessels (PGMV) via A 2A receptors. In: British Journal of Pharmacology. 2004 ; Vol. 141, No. 3. pp. 441-448.
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AU - Cheng, M. K.

AU - Doumad, A. B.

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AU - McGiff, J. C.

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N2 - 1. Activation of rat adenosine 2A receptors (A 2A R) dilates preglomerular microvessels (PGMV), an effect mediated by epoxyeicosatrienoic acids (EETs). 2. Incubation of PGMV with a selective A 2A R agonist, 2-p-(2-carboxyethyl) phenethylamino-5′-N- ethylcarboxamidoadenosine (CGS 21680; 100 μM), increased isolated PGMV EET levels to 7.57±1.53 ng mg -1 protein from 1.06±0.22 ng mg -1 protein in controls (P<0.05), without affecting hydroxyeicosatetraenoic acid (HETE) levels (10.8±0.69 vs 11.02±0.74 ng mg -1 protein). 3. CGS 21680-stimulated EETs was abolished by preincubation with an A 2A R antagonist, 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl) phenol (ZM241385) (100 μM). A selective epoxygenase inhibitor, methylsulfonyl-propargyloxyphenylhexanamide (MS-PPOH; 12 μM) prevented CGS 21680-induced increase in EETs, indicating inhibition of de novo synthesis of EETs. 4. In pressurized (80 mmHg) renal arcuate arteries (110-130 μm) preconstricted with phenylephrine (20 nM), superfusion with CGS 21680 (0.01-10 μM) increased the internal diameter (i.d.) concentration-dependently; vasodilation was independent of nitric oxide and cyclooxygenase activity. CGS 21680 (10 μM) increased i.d. by 32±6 μm; vasodilation was prevented by inhibition of EET synthesis with MS-PPOH. 5. Addition of 3nM 5,6-EET, 8,9-EET and 11,12-EET increased i.d. by 53±9, 17±4 and 53±5 μm, respectively, whereas 14,15-EET was inactive. The responses to 5,6-EET were, however, significantly inhibited by indomethacin. 6. We conclude that 11,12-EET is the likely mediator of A 2A R-induced dilation of rat PGMV. Activation of A 2A R coupled to de novo EET stimulation may represent an important mechanism in regulating preglomerular microvascular tone.

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KW - A receptors

KW - A receptors

KW - Adenosine

KW - Cytochrome P450

KW - Rat renal artery

KW - Renal EETs

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