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Exaggerated vasoconstriction depends on ω‐hydroxyylase through adenosine A 1 receptor (AR) in A 1 WT compared to A 1 KO mouse aorta
Author(s) -
Kunduri Swati Sarada,
Nayeem Mohammad,
Falck John,
Schnermann Jurgen,
Mustafa S.Jamal
Publication year - 2010
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.24.1_supplement.958.3
Subject(s) - vasoconstriction , chemistry , arachidonic acid , adenosine , medicine , vasodilation , contraction (grammar) , endocrinology , ccpa , agonist , vascular smooth muscle , metabolite , aorta , adenosine receptor , receptor , biochemistry , enzyme , biology , smooth muscle
Adenosine exerts its vasoconstrictor effect with the activation of A 1 AR through PLC‐βIII → PKCα → p42/44 pathway, and possibly arachidonic acid derived metabolite (20‐HETE) generated through hydroxylation via CYP4A enzyme in vascular smooth muscle cells. 20‐HETE plays an important role in the regulation of vascular tone in a number of vascular beds. We hypothesize that the A 1 AR‐mediated vasoconstriction depends on CYP4A hydroxylation of arachidonic acid. Organ bath experiments with aorta from A 1 WT and A 1 KO mice were used in this study. The tissues were contracted with 10 −6 M PE and the intactness of endothelium was tested with 10 −6 M ACh. Tissues that relaxed >40% were used in this study. A 1 KO had significantly higher ACh relaxation (+72.38±14.07%) than A 1 WT (52.76±11.87%). CRC to a non‐selective adenosine analog (NECA) and an A 1 AR selective agonist (CCPA, 10 −6 M) were obtained with CYP4A inhibitors (HET‐0016, 10 −6 and DDMS, 10 −5 M). HET‐0016 changed the NECA (−19.51 ± 3.68%) and CCPA‐induced contraction (−34.08± 5.68%) into relaxation (60.36± 13.7 %). DDMS changed CCPA (10 −6 M) induced contraction (−29.83 ± 7.19%) into relaxation (18.79± 5.19%). CYP expoxygenase inhibitor (MSPPOH, 10 −5 M) caused significantly higher contraction in the treated group (−50.46± 6.25%) vs the control (−20.46± 4.82%). These data support a role for CYP4A in A 1 AR‐mediated vasoconstriction. Supported by HL027339, HL09444, GM31278