期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 295, 期 5, 页码 H2068-H2078出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.01333.2007
关键词
epoxyeicosatrienoic acids; dihydroxyeicosatrienoic acids; vasodilation; vasoconstriction; adenosine; cytochrome P-450s
资金
- National Institutes of Health [HL027339, HL-094447, GM-31278, RO1-NS-052315, S10-RR-023461]
- Intramural Research Program of the National Institute of Environmental Health Sciences
Nayeem MA, Poloyac SM, Falck JR, Zeldin DC, Ledent C, Ponnoth DS, Ansari HR, Mustafa SJ. Role of CYP epoxygenases in A(2A)AR-mediated relaxation using A(2A)AR-null and wild-type mice. Am J Physiol Heart Circ Physiol 295: H2068-H2078, 2008. First published September 19, 2008; doi: 10.1152/ajpheart.01333.2007.-We hypothesized that A(2A) adenosine receptor (A(2A)AR) activation causes vasorelaxation through cytochrome P-450 (CYP) epoxygenases and endothelium-derived hyperpolarizing factors, whereas lack of A(2A)AR activation promotes vasoconstriction through Cyp4a in the mouse aorta. Adenosine 5'-N-ethylcarboxamide (NECA; 10(-6) M), an adenosine analog, caused relaxation in wild-type A(2A)AR (A(2A)AR(+/+); + 33.99 +/- 4.70%, P < 0.05) versus contraction in A(2A)AR knockout (A(2A)AR(+/+); + 27.52 +/- 4.11%) mouse aortae. An A(2A)AR-specific antagonist (SCH-58261; 1 mu M) changed the NECA (10(-6) M) relaxation response to contraction (-35.82 +/- 4.69%, P < 0.05) in A(2A)AR(+/+) aortae, whereas no effect was noted in A(2A)AR(-/-) aortae. Significant contraction was seen in the absence of the endothelium in A(2A)AR(+/+) (-2.58 +/- 2.25%) aortae compared with endothelium intact aortae. An endothelial nitric oxide synthase inhibitor (N-nitroL-arginine methyl ester; 100 mu M) and a cyclooxygenase inhibitor (indomethacin; 10 mu M) failed to block NECA-induced relaxation in A(2A)AR(-/-) aortae. A selective inhibitor of CYP epoxygenases (methylsulfonyl-propargyloxyphenylhexanamide; 10(-6) M) changed NECA-mediated relaxation (-22.74 +/- 5.11% at 10(-6) M) and CGS-21680 mediated relaxation (-18.54 +/- 6.06% at 10 - 6 M) to contraction in A(2A)AR(+/+) aortae, whereas no response was noted in A(2A)AR(-/-) aortae. Furthermore, an epoxyeicosatrienoic acid (EET) antagonist [14,15-epoxyeicosa-5(Z)-enoic acid; 10 mu M] was able to block NECAinduced relaxation in A(2A)AR(+/+) aortae, whereas omega-hydroxylase inhibitors (10 mu M dibromo-dodecenyl-methylsulfimide and 10 mu M HET-0016) changed contraction into relaxation in A(2A)AR (-/-) aorta. Cyp2c29 protein was upregulated in A(2A)AR(+/+) aortae, whereas Cyp4a was upregulated in A(2A)AR(-/-) aortae. Higher levels of dihydroxyeicosatrienoic acids (DHETs; 14,15-DHET, 11,12-DHET, and 8,9-DHET, P < 0.05) were found in A(2A)AR(+/+) versus A(2A)AR(-/-) aortae. EET levels were not significantly different between A(2A)AR(+/+) and A(2A)AR(-/-) aortae. It is concluded that CYP epoxygenases play an important role in A(2A)AR-mediated relaxation, and the deletion of the A(2A)AR leads to contraction through Cyp4a.
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