5,6-epoxyeicosatrienoic acid mediates the enhanced renal vasodilation to arachidonic acid in the SHR.
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 Nw-nitro-L-arginine (50 micromol/L), whereas the responses to high doses were unaffected. Inhibition of epoxygenases with miconazole (0.3 micromol/L) in the presence of Nw-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.
Pomposiello
Silvia I
SI
Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
Quilley
John
J
Carroll
Mairead A
MA
Falck
John R
JR
McGiff
John C
JC
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects; D008297:Male; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D019789:Tetraethylammonium / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D014665:Vasodilator Agents; D016718:Arachidonic Acid; D019789:Tetraethylammonium; C040776:5,6-epoxy-8,11,14-eicosatrienoic acid; D003577:Cytochrome P-450 Enzyme System; D015126:8,11,14-Eicosatrienoic Acid