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Role of CYP2C generated metabolites in adenosine‐mediated relaxation using A2A AR−/− mice
Author(s) -
Nayeem Mohammed A.,
Poloyac Samuel M.,
Falck John R.,
Zeldin Darryl C.,
Ledent Catherine,
Mustafa S. Jamal
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.964.23
Subject(s) - aorta , contraction (grammar) , medicine , adenosine a2a receptor , cgs 21680 , chemistry , adenosine , endocrinology , adenosine receptor , receptor , agonist
We hypothesize that A2A‐adenosine receptor (A2A AR)‐mediated relaxation is caused by CYP2C generated metabolites whereas, lack of A2A AR promotes contraction via CYP4A in mouse aorta. We measured EETs and DHETs in A2A AR+/+ /A2A AR−/− aorta. DHETs were significantly higher in A2A AR+/+ vs. A2A AR−/− aorta (14,15‐DHET: 1.66±0.25 vs. 0.83±0.17; 11,12‐DHET: 1.39±0.20 vs. 0.84±0.12; 8,9‐DHET: 0.89±0.15 vs. 0.35±0.08 pmol/mg/min p<0.05). No significant differences were observed in EET levels in A2A AR+/+ vs. A2A AR−/− aorta. CYP2C29 was higher in A2A AR+/+ aorta (p<0.05) while CYP4A was higher in A2A AR−/− aorta (p<0.05). CYP2C inhibitor, 1‐ABT (5μM) changed the response to NECA (10‐6M) from relaxation (+33.99±4.70%) to contraction (25.70±4.75%, p<0.05) in A2A AR+/+. Similar results were obtained in A2A AR+/+ to NECA at 10‐6 M with selective CYP2C inhibitor MS‐PPOH (10μM, 22.74±5.11%, p<0.05). 1‐ABT also changed the response of CGS 21680 (10‐6M) from relaxation (+28.44±4.36%) to contraction (18.60±4.66%, p<0.05) in A2A AR+/+. In contrast, no effect was seen in A2A AR−/− with 1‐ABT and MS‐PPOH. MS‐PPOH also caused contraction to CGS 21680 at 10‐6M (−18.54±6.06%, p<0.05) in A2A AR+/+, while 1‐ABT and MS‐PPOH were without an effect in A2A AR−/−. The data show that CYP2C generated metabolites play an important role in A2A AR‐mediated relaxation, whereas, in A2A AR−/−, CYP4A induces contraction. Supported by HL027339, GM31278, NIEHS, NS052315, S10RR023461, S10RR023461 & NS052315.