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(Hypertension. 2003;42:837.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Role of COX-2 in the Enhanced Vasoconstrictor Effect of Arachidonic Acid in the Diabetic Rat Kidney

From the Department of Pharmacology, New York Medical College, Valhalla, NY.

Correspondence to John Quilley, PhD, Department of Pharmacology, New York Medical College, Valhalla, NY 10595. E-mail john_quilley{at}nymc.edu

In the rat isolated perfused kidney, arachidonic acid elicits cyclooxygenase-dependent vasoconstriction through activation of PGH₂/TxA₂ receptors; responses are enhanced in kidneys from diabetic rats. This study examined the roles of cyclooxygenase-1/cyclooxygenase-2 in the enhanced renal vasoconstrictor effect of arachidonic acid in streptozotocin-diabetic rats. Release of 20-HETE was also determined, as this eicosanoid has been reported to elicit cyclooxygenase-dependent vasoconstriction. We confirmed that vasoconstrictor responses to arachidonic acid were enhanced in the diabetic rat kidney associated with a 2-fold–greater increase in the release of 6-ketoPGF₁, which was used as an index of cyclooxygenase activity. One and three micrograms of arachidonic acid increased perfusion pressure by 85±37 and 186±6 mm Hg, respectively, in diabetic rat kidneys compared with 3±1 and 17±8 mm Hg, respectively, in control rat kidneys. Inhibition of both cyclooxygenase isoforms with indomethacin (10 µmol/L) abolished the vasoconstrictor response to arachidonic acid in both diabetic and control rat kidneys, whereas inhibition of cyclooxygenase-2 with nimesulide (5µmol/L) reduced perfusion pressure responses to 1 and 3 µg arachidonic acid only in the diabetic rat kidney to 15±8 and 108±26 mm Hg, respectively, consistent with a 3-fold increase in the renal cortical expression of cyclooxygenase-2. 20-HETE release from the diabetic rat kidney was reduced almost 6-fold and was not increased in response to arachidonic acid. These results demonstrate that the renal vasoconstrictor effect of arachidonic acid is solely dependent on cyclooxygenase activity, with no evidence for a contribution from 20-HETE; in the diabetic rat, cyclooxygenase-2 activity contributes to the renal vasoconstrictor effect of arachidonic acid.

Key Words: diabetes mellitus • kidney • cyclooxygenase • vasculature • arachidonic acid

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