(Hypertension. 2001;37:887.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Epoxyeicosatrienoic Acid–Mediated Renal Vasodilation to Arachidonic Acid Is Enhanced in SHR
From the Department of Pharmacology (S.I.P, M.A.C., J.C.M.), New York Medical College, Valhalla, and the Department of Biochemistry (J.R.F.), University of Texas Southwestern Medical Center, Dallas.
Correspondence to John C. McGiff, MD, Department of Pharmacology, New York Medical College, Valhalla, NY 10595. E-mail John_McGiff{at}nymc.edu
We
tested the hypothesis that
cyclooxygenase-independent vasodilation produced by
arachidonic acid (AA) is mediated by
epoxyeicosatrienoic acids (EETs) and is blunted in the spontaneously
hypertensive rat (SHR). At normal perfusion pressure (PP; 70 to
90 mm Hg), AA constricted the renal vasculature in both SHR and
normotensive Wistar-Kyoto rats, an effect abolished by
cyclooxygenase inhibition, and converted to
vasodilation when PP was raised to 
200 mm Hg. Unexpectedly,
renal vasodilation elicited by AA was greater in the SHR at high PP;
for example, 2.5, 5, and 10 µg of AA produced PP declines of 54±9,
92±10, and 112±5 mm Hg, respectively, in SHR compared with
26±3, 45±5, and 77±6 mm Hg in Wistar-Kyoto rats
(P<0.01). However, the renal
vasodilator responses to acetylcholine (0.1 µg) and sodium
nitroprusside (1 µg) did not differ between strains, indicating that
vascular responsiveness to AA was independent of intrinsic changes in
vascular smooth muscle. Hyperresponsiveness of the renal vasculature to
AA may be unique for the SHR, because it did not occur in
Sprague-Dawley rats with angiotensin II–induced
hypertension. 5,8,11,14-Eicosatetraynoic acid (ETYA; 4 µmol/L), an
inhibitor of all AA pathways, attenuated the vasodilator
responses to AA, as did treatment with stannous chloride, which
depletes cytochrome P450 enzymes, suggesting that a cytochrome P450 AA
metabolite mediated the renal vasodilation.
N-Methylsulfonyl-12,12-dibromododec-11-en-amide
(DDMS; 2 µmol/L), a selective 
-hydroxylase inhibitor,
did not affect AA-induced vasodilation, whereas selective inhibition of
epoxygenases with either miconazole (0.3 µmol/L) or
N-methylsulfonyl-6-(2-propargyloxyphenyl)
hexanamide (MS-PPOH; 12 µmol/L) did, indicating that one or more EETs
were involved in the renal vasodilator action of AA at high PP. This
conclusion was supported by the demonstration that AA greatly enhanced
the renal efflux of EETs at high PP but not at basal
PP.
Key Words: hypertension, renal • kidney • arachidonic acid • vasodilation
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