Transfection of CYP4A1 cDNA increases vascular reactivity in renal interlobar arteries
20-HETE, a cytochrome P-450 4A (CYP4A1)-derived arachidonic acid metabolite, is a major eicosanoid formed in renal and extrarenal microcirculation. 20-HETE inhibits Ca(2+)-activated K(+) channels in vascular smooth muscle cells and thereby may modulate vascular reactivity. We transfected renal inter...
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Published in | American journal of physiology. Renal physiology Vol. 284; no. 1; pp. F51 - F56 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
01.01.2003
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Subjects | |
Online Access | Get full text |
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Summary: | 20-HETE, a cytochrome P-450 4A (CYP4A1)-derived arachidonic acid metabolite, is a major eicosanoid formed in renal and extrarenal microcirculation. 20-HETE inhibits Ca(2+)-activated K(+) channels in vascular smooth muscle cells and thereby may modulate vascular reactivity. We transfected renal interlobar arteries with an expression plasmid containing the cDNA of CYP4A1, the low-K(m) arachidonic acid omega-hydroxylase, and examined the consequences of increasing 20-HETE synthesis on constrictor responses to phenylephrine. CYP4A1-transfected interlobar arteries demonstrated a twofold increase in CYP4A protein levels and 20-HETE production compared with arteries transfected with the empty plasmid; they also showed increased sensitivity to phenylephrine, as evidenced by a decrease in EC(50) from 0.37 +/- 0.04 microM in plasmid-transfected arteries to 0.07 +/- 0.01 microM in CYP4A1-transfected arteries. The increased sensitivity to phenylephrine was greatly attenuated by N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), a selective inhibitor of 20-HETE synthesis, and by 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid, a specific 20-HETE antagonist. This effect of DDMS was reversed by addition of 20-HETE, further substantiating the notion that increased levels of 20-HETE contribute to the increased sensitivity to phenylephrine in vessels overexpressing CYP4A1. These data suggest that 20-HETE of vascular origin sensitizes renal vascular smooth muscle to phenylephrine. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1931-857X 1522-1466 |
DOI: | 10.1152/ajprenal.00249.2002 |