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Am J Physiol Renal Physiol 284: F51-F56, 2003. First published September 3, 2002; doi:10.1152/ajprenal.00249.2002
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Vol. 284, Issue 1, F51-F56, January 2003

Transfection of CYP4A1 cDNA increases vascular reactivity in renal interlobar arteries

Jun-Ichi Kaide1, Mong-Heng Wang1, Ji-Shi Wang1, Fan Zhang1, V.Raj Gopal2, John R. Falck2, Alberto Nasjletti1, and Michal Laniado-Schwartzman1

1 Department of Pharmacology, New York Medical College, Valhalla, New York 10595; and 2 Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75235

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 Ca2+-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-Km 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 EC50 from 0.37 ± 0.04 µM in plasmid-transfected arteries to 0.07 ± 0.01 µM 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.

20-hydroxyeicosatetraenoic acid; arachidonic acid; phenylephrine; cytochrome P-450


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