Published Online
on August 25, 2003

A more recent version of this article appeared on October 1, 2003

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Submitted on February 6, 2003
Revised on February 28, 2003

5,6-Epoxyeicosatrienoic Acid Mediates the Enhanced Renal Vasodilation to Arachidonic Acid in the SHR

Silvia I. Pomposiello; John Quilley; Mairead A. Carroll; John R. Falck; and John C. McGiff^*

From the Department of Pharmacology, New York Medical College (J.Q., M.A.C., J.C.M.), Valhalla; Pharmacia (S.I.P.), St Louis, Mo; and the Department of Biochemistry, University of Texas Southwestern Medical Center (J.R.F.), Dallas.

^* To whom correspondence should be addressed. E-mail: John_McGiff{at}nymc.edu.

Abstract--We have shown a cytochrome P450-dependent renal vasodilator effect of arachidonic acid in response to inhibition of cyclooxygenase and elevation of perfusion pressure, which was enhanced in the spontaneously hypertensive rat (SHR) and linked to increased production of and/or responsiveness to epoxyeicosatrienoic acids (EETs). In the SHR, vasodilation elicited by low doses of arachidonic acid was attenuated by the nitric oxide synthase inhibitor N^w-nitro-L-arginine (50 µmol/L), whereas the responses to high doses were unaffected. Inhibition of epoxygenases with miconazole (0.3 µmol/L) in the presence of N^w-nitro-L-arginine greatly reduced the renal vasodilator response to all doses of arachidonic acid. Tetraethylammonium (10 mmol/L), a nonselective K⁺ channel blocker, abolished the nitric oxide-independent renal vasodilator effect of arachidonic acid as well as the vasodilator effect of 5,6-EET, confirming that EET-dependent vasodilation involves activation of K⁺ channels. Under conditions of elevated perfusion pressure (200 mm Hg) and cyclooxygenase inhibition, 5,6-EET, 8, 9-EET, and 11,12-EET caused renal vasodilatation in both SHR and Wistar-Kyoto rats (WKY), whereas 14,15-EET produced vasoconstriction. 5,6-EET was the most potent renal vasodilator of the EET regioisomers in the SHR by a factor of 4 or more. In the SHR, 5,6-EET- and 11,12-EET-induced renal vasodilatation was >2-fold greater than that registered in WKY. Thus, the augmented vasodilator responses to arachidonic acid in the SHR is through activation of K⁺ channels, and 5,6-EET is the most likely mediator.

Key words: kidney • rats, spontaneously hypertensive • cytochrome P450 • arachidonic acids • vasodilation

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