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Articles in PresS, published online ahead of print September 3, 2002
Am J Physiol Renal Physiol, 10.1152/ajprenal.00249.2002
Submitted on July 9, 2002
Accepted on August 23, 2002
1 Department of Pharmacology, New York Medical College, Valhalla, NY, USA
2 Department of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA
* To whom correspondence should be addressed. E-mail: michal_schwartzman{at}nymc.edu.
20-hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P450 (CYP) 4A-derived arachidonic acid metabolite, is a major eicosanoid formed in the 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 the CYP4A1, the low Km arachidonic acid 
-hydroxylase, and examined the consequences of increasing 20-HETE synthesis on constrictor responses to phenylephrine. CYP4A1-transfected interlobar arteries demonstrated a 2-fold increase in CYP4A protein levels and 20-HETE production compared to 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 in plasmid-transfected arteries to 0.07±0.01µM 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 (20-HEDE), 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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