Cyclooxygenase dependency of the renovascular actions of cytochrome P450- derived arachidonate metabolites

M. A. Carroll, M. P. Garcia, J R Falck, J. C. McGiff

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Abstract

The renovascular effects of cytochrome P450-dependent arachidonic acid (P450-AA) metabolites synthesized by rat and rabbit kidneys were studied in the rabbit isolated kidney under conditions of constant flow and examined for their dependency on cyclooxygenase relative to their expression of vasoactivity. Kidneys were perfused with Krebs-Henseleit solution, and perfusion pressure was raised to levels of 90 to 110 mm Hg with the addition of 2 to 3 μM phenylephrine to the perfusate. Close arterial injection of 1 to 20 μg of 5,6-, 8,9- and 11,12-epoxyeicosatrienoic acid (EET) dose- dependently decreased perfusion pressure. The 5,6-EET was the most potent and the only epoxide dependent on cyclooxygenase for expression of vasoactivity, being inhibited by indomethacin (2.8 μM). In contrast, 14,15-EET resulted in dose-dependent increases in perfusion pressure. The vasodilator effects of the ω- and ω-1 oxidation products, 20-hydroxyeicosatetraenoic acid (HETE) and the stereoisomers of 19-HETE, were also inhibited by indomethacin. Furthermore, the renal vasodilator responses to 5,6-EET were not inhibited by either superoxide dismutase (10 U) or catalase (40 U) and, therefore, were unrelated to the formation of oxygen radicals generated during transformation of the epoxide by cyclooxygenase. As 5,6-EET and 19- and 20-HETE are synthesized by the renal tubules and can affect movement of salt and water, expression of vasoactivity by P450-dependent arachidonic acid metabolites, and after release from a nephron segment, may represent a mechanism that couples altered renal tubular function to appropriate changes in local blood flow.

Original languageEnglish (US)
Pages (from-to)104-109
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume260
Issue number1
StatePublished - 1992

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Prostaglandin-Endoperoxide Synthases
Cytochrome P-450 Enzyme System
Kidney
Perfusion
Epoxy Compounds
Vasodilator Agents
Pressure
Arachidonic Acid
Indomethacin
Rabbits
Water Movements
Hydroxyeicosatetraenoic Acids
Stereoisomerism
Nephrons
Phenylephrine
Catalase
Superoxide Dismutase
Reactive Oxygen Species
Salts
Injections

ASJC Scopus subject areas

  • Pharmacology

Cite this

Cyclooxygenase dependency of the renovascular actions of cytochrome P450- derived arachidonate metabolites. / Carroll, M. A.; Garcia, M. P.; Falck, J R; McGiff, J. C.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 260, No. 1, 1992, p. 104-109.

Research output: Contribution to journalArticle

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