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(Hypertension. 2005;45:103.)
© 2005 American Heart Association, Inc.

Scientific Contributions

Decreased Levels of Cytochrome P450 2E1–Derived Eicosanoids Sensitize Renal Arteries to Constrictor Agonists in Spontaneously Hypertensive Rats

Fan Zhang; Huan Deng; Rowena Kemp; Harpreet Singh; Venkat Raj Gopal; John R. Falck; Michal Laniado-Schwartzman; Alberto Nasjletti

From the Department of Pharmacology (F.Z., H.D., R.K., H.S., M.L.-S., A.N.), New York Medical College, Valhalla, NY; and Departments of Biochemistry and Pharmacology (V.R.G., J.R.F.), University of Texas Southwestern Medical School, Dallas.

Correspondence to Alberto Nasjletti, MD, Department of Pharmacology, New York Medical College, Valhalla, NY 10595. E-mail alberto_nasjletti{at}nymc.edu

We compared renal interlobar arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) in terms of cytochrome P450 (CYP) 4A and CYP2E1 protein expression; levels of 20-HETE, 19-HETE, and 18-HETE; and responsiveness to phenylephrine in the absence and presence of N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS; 30 µmol/L), a CYP4A inhibitor. Relative to data in WKY, arteries of SHR exhibited diminished (P<0.05) CYP2E1 and levels of 19-HETE (66.7±6.0 versus 44.9±2.8 pmol/mg) and 18-HETE (13.8±1.6 versus 7.9±0.5 pmol/mg), whereas CYP4A and 20-HETE levels (99.3±9.1 versus 98.9±12.8 pmol/mg) were unchanged. Phenylephrine contracted vascular rings of SHR and WKY; the R_max was similar in both strains, but SHR vessels were more sensitive as denoted by the lower (P<0.05) EC₅₀ (0.28±0.07 versus 0.71±0.12 µmol/L). DDMS decreased 20-HETE and, to a lesser extent, 19-HETE, while increasing (P<0.05) the EC₅₀ for phenylephrine by 475% and 54% in vessels of SHR and WKY, respectively. The desensitizing effect of DDMS was reversed by 20-HETE. Notably, the minimal concentration of 20-HETE that decreased the EC₅₀ for phenylephrine in DDMS-treated vessels was smaller in SHR (0.1 µmol/L) than WKY (10 µmol/L), and the sensitizing effect of 20-HETE was blunted (P<0.05) by the (R) stereoisomers of 19-HETE and 18-HETE. We conclude that the increased sensitivity to phenylephrine in arteries of SHR is attributable to a vasoregulatory imbalance produced by a deficit in vascular CYP2E1-derived products, most likely 19(R)-HETE and 18(R)-HETE, which condition amplification of the sensitizing action of 20-HETE.

Key Words: rats, spontaneously hypertensive • vasoconstriction • kidney

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