TY - JOUR
T1 - Decreased levels of cytochrome P450 2E1-derived eicosanoids sensitize renal arteries to constrictor agonists in spontaneously hypertensive rats
AU - Zhang, Fan
AU - Deng, Huan
AU - Kemp, Rowena
AU - Singh, Harpreet
AU - Gopal, Venkat Raj
AU - Falck, John R.
AU - Laniado-Schwartzman, Michal
AU - Nasjletti, Alberto
PY - 2005/1
Y1 - 2005/1
N2 - 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.
AB - 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.
KW - Kidney
KW - Rats, spontaneously hypertensive
KW - Vasoconstriction
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UR - http://www.scopus.com/inward/citedby.url?scp=11244346108&partnerID=8YFLogxK
U2 - 10.1161/01.HYP.0000150782.28485.91
DO - 10.1161/01.HYP.0000150782.28485.91
M3 - Article
C2 - 15569854
AN - SCOPUS:11244346108
SN - 0194-911X
VL - 45
SP - 103
EP - 108
JO - Hypertension
JF - Hypertension
IS - 1
ER -