title: Decreased levels of cytochrome P450 2E1-derived eicosanoids sensitize renal arteries to constrictor agonists in spontaneously hypertensive rats.
abstract: 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 mumol/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 mumol/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 micromol/L) than WKY (10 micromol/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.
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Huan
authors.initials: H
authors.lastname: Deng
authors.forename: Rowena
authors.initials: R
authors.lastname: Kemp
authors.forename: Harpreet
authors.initials: H
authors.lastname: Singh
authors.forename: Venkat Raj
authors.initials: VR
authors.lastname: Gopal
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Michal
authors.initials: M
authors.lastname: Laniado-Schwartzman
authors.forename: Alberto
authors.initials: A
authors.lastname: Nasjletti
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D042926:Cytochrome P-450 CYP4A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006893:Hydroxyeicosatetraenoic Acids / Q000172:deficiency*; D006973:Hypertension / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D010656:Phenylephrine / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012077:Renal Artery / Q000187:drug effects / Q000201:enzymology*; D013450:Sulfones / Q000494:pharmacology; D019789:Tetraethylammonium / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014667:Vasopressins / Q000494:pharmacology
chemical_list: D000577:Amides; D006893:Hydroxyeicosatetraenoic Acids; D026902:Potassium Channel Blockers; D013450:Sulfones; D014662:Vasoconstrictor Agents; D014667:Vasopressins; D010656:Phenylephrine; C061444:18-hydroxy-5,8,11,14-eicosatetraenoic acid; D016718:Arachidonic Acid; D019789:Tetraethylammonium; C055986:19-hydroxy-5,8,11,14-eicosatetraenoic acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; C117975:DDMS; D019392:Cytochrome P-450 CYP2E1; D042926:Cytochrome P-450 CYP4A