Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1989 Dec;84(6):1805–1812. doi: 10.1172/JCI114365

Cytochrome P450 metabolites of arachidonic acid are potent inhibitors of vasopressin action on rabbit cortical collecting duct.

D L Hirt 1, J Capdevila 1, J R Falck 1, M D Breyer 1, H R Jacobson 1
PMCID: PMC304058  PMID: 2556446

Abstract

AA is metabolized by a cytochrome P450, NADPH-dependent epoxygenase to four regioisomeric epoxyeicosatrienoic acids (EETs). The EETs are further hydrated enzymatically to their respective diols, vic-dihydroxyeicosatrienoic acids (DHETs). We studied the effect of pretreatment with DHETs on 10 microU/cm2 arginine vasopressin (AVP)-stimulated hydraulic conductivity (Lp) (Lp x 10(-7) cm/atm/s, mean +/- SE) in rabbit cortical collecting ducts (CCDs) perfused in vitro at 37 degrees C. At 10(-6) M all four DHETs were potent inhibitors of the hydroosmotic effect of AVP. 14,15-DHET was the most potent isomer; it reduced AVP-induced Lp from a control value of 234.75 +/- 11.7, n = 17, to a value of 95.2 +/- 8.39, n = 5, P less than 0.0001, a reduction of AVP-mediated water flow of 60%. The inhibitory effect of 14,15-DHET was dose dependent and significant to nanomolar concentrations. 14,15-DHET at 10(-7) M was as potent an inhibitor of AVP's activity as was 10(-7) M PGE2. AVP's hydroosmotic effect is mediated through its intracellular second messenger, cAMP. 8-p-Chlorophenylthio-cAMP (CcAMP) at 10(-4) M induced a peak Lp of 189.6 +/- 11.0, n = 8; pretreatment with 10(-6) M 14,15-DHET reduced CcAMP-peak Lp to 132.0 +/- 13.4, n = 5, P less than 0.01, demonstrating a post-cAMP effect. Gas chromatography/mass spectroscopy suggests that EETs are present in extracts purified from CCDs. We conclude that cytochrome P450 epoxygenase eicosanoids are potent inhibitors of the hydroosmotic effect of vasopressin and are endogenous constituents of normal CCDs, the major target tissue for AVP.

Full text

PDF
1806

Images in this article

1808Image
on p.1808
1808Image
on p.1808
1808Image
on p.1808
1809Image
on p.1809

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ando Y., Jacobson H. R., Breyer M. D. Phorbol myristate acetate, dioctanoylglycerol, and phosphatidic acid inhibit the hydroosmotic effect of vasopressin on rabbit cortical collecting tubule. J Clin Invest. 1987 Aug;80(2):590–593. doi: 10.1172/JCI113110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bonvalet J. P., Pradelles P., Farman N. Segmental synthesis and actions of prostaglandins along the nephron. Am J Physiol. 1987 Sep;253(3 Pt 2):F377–F387. doi: 10.1152/ajprenal.1987.253.3.F377. [DOI] [PubMed] [Google Scholar]
  3. Burg M., Grantham J., Abramow M., Orloff J. Preparation and study of fragments of single rabbit nephrons. Am J Physiol. 1966 Jun;210(6):1293–1298. doi: 10.1152/ajplegacy.1966.210.6.1293. [DOI] [PubMed] [Google Scholar]
  4. Capdevila J. H., Kishore V., Dishman E., Blair I. A., Falck J. R. A novel pool of rat liver inositol and ethanolamine phospholipids contains epoxyeicosatrienoic acids (EETs). Biochem Biophys Res Commun. 1987 Jul 31;146(2):638–644. doi: 10.1016/0006-291x(87)90576-6. [DOI] [PubMed] [Google Scholar]
  5. Capdevila J., Chacos N., Werringloer J., Prough R. A., Estabrook R. W. Liver microsomal cytochrome P-450 and the oxidative metabolism of arachidonic acid. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5362–5366. doi: 10.1073/pnas.78.9.5362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Capdevila J., Marnett L. J., Chacos N., Prough R. A., Estabrook R. W. Cytochrome P-450-dependent oxygenation of arachidonic acid to hydroxyicosatetraenoic acids. Proc Natl Acad Sci U S A. 1982 Feb;79(3):767–770. doi: 10.1073/pnas.79.3.767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Carroll M. A., Schwartzman M., Capdevila J., Falck J. R., McGiff J. C. Vasoactivity of arachidonic acid epoxides. Eur J Pharmacol. 1987 Jun 19;138(2):281–283. doi: 10.1016/0014-2999(87)90445-6. [DOI] [PubMed] [Google Scholar]
  8. Currie M. G., Needleman P. Renal arachidonic acid metabolism. Annu Rev Physiol. 1984;46:327–341. doi: 10.1146/annurev.ph.46.030184.001551. [DOI] [PubMed] [Google Scholar]
  9. Du Bois R., Vernoiry A., Abramow M. Computation of the osmotic water permeability of perfused tubule segments. Kidney Int. 1976 Dec;10(6):478–479. doi: 10.1038/ki.1976.135. [DOI] [PubMed] [Google Scholar]
  10. Falck J. R., Schueler V. J., Jacobson H. R., Siddhanta A. K., Pramanik B., Capdevila J. Arachidonate epoxygenase: identification of epoxyeicosatrienoic acids in rabbit kidney. J Lipid Res. 1987 Jul;28(7):840–846. [PubMed] [Google Scholar]
  11. Fitzpatrick F. A., Ennis M. D., Baze M. E., Wynalda M. A., McGee J. E., Liggett W. F. Inhibition of cyclooxygenase activity and platelet aggregation by epoxyeicosatrienoic acids. Influence of stereochemistry. J Biol Chem. 1986 Nov 15;261(32):15334–15338. [PubMed] [Google Scholar]
  12. Fitzpatrick F. A., Murphy R. C. Cytochrome P-450 metabolism of arachidonic acid: formation and biological actions of "epoxygenase"-derived eicosanoids. Pharmacol Rev. 1988 Dec;40(4):229–241. [PubMed] [Google Scholar]
  13. Grantham J. J., Orloff J. Effect of prostaglandin E1 on the permeability response of the isolated collecting tubule to vasopressin, adenosine 3',5'-monophosphate, and theophylline. J Clin Invest. 1968 May;47(5):1154–1161. doi: 10.1172/JCI105804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kutsky P., Falck J. R., Weiss G. B., Manna S., Chacos N., Capdevila J. Effects of newly reported arachidonic acid metabolites on microsomal Ca++ binding, uptake and release. Prostaglandins. 1983 Jul;26(1):13–21. doi: 10.1016/0090-6980(83)90070-9. [DOI] [PubMed] [Google Scholar]
  15. McGiff J. C., Carroll M. A. Cytochrome P-450-related arachidonic acid metabolites. Am Rev Respir Dis. 1987 Aug;136(2):488–491. doi: 10.1164/ajrccm/136.2.488. [DOI] [PubMed] [Google Scholar]
  16. Nadler S. P., Hebert S. C., Brenner B. M. PGE2, forskolin, and cholera toxin interactions in rabbit cortical collecting tubule. Am J Physiol. 1986 Jan;250(1 Pt 2):F127–F135. doi: 10.1152/ajprenal.1986.250.1.F127. [DOI] [PubMed] [Google Scholar]
  17. Negro-Vilar A., Snyder G. D., Falck J. R., Manna S., Chacos N., Capdevila J. Involvement of eicosanoids in release of oxytocin and vasopressin from the neural lobe of the rat pituitary. Endocrinology. 1985 Jun;116(6):2663–2668. doi: 10.1210/endo-116-6-2663. [DOI] [PubMed] [Google Scholar]
  18. Oliw E. H., Guengerich F. P., Oates J. A. Oxygenation of arachidonic acid by hepatic monooxygenases. Isolation and metabolism of four epoxide intermediates. J Biol Chem. 1982 Apr 10;257(7):3771–3781. [PubMed] [Google Scholar]
  19. Schlondorff D., Ardaillou R. Prostaglandins and other arachidonic acid metabolites in the kidney. Kidney Int. 1986 Jan;29(1):108–119. doi: 10.1038/ki.1986.13. [DOI] [PubMed] [Google Scholar]
  20. Schlondorff D., Levine S. D. Inhibition of vasopressin-stimulated water flow in toad bladder by phorbol myristate acetate, dioctanoylglycerol, and RHC-80267. Evidence for modulation of action of vasopressin by protein kinase C. J Clin Invest. 1985 Sep;76(3):1071–1078. doi: 10.1172/JCI112060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Schlondorff D., Petty E., Oates J. A., Jacoby M., Levine S. D. Epoxygenase metabolites of arachidonic acid inhibit vasopressin response in toad bladder. Am J Physiol. 1987 Sep;253(3 Pt 2):F464–F470. doi: 10.1152/ajprenal.1987.253.3.F464. [DOI] [PubMed] [Google Scholar]
  22. Schuster V. L. Mechanism of bradykinin, ADH, and cAMP interaction in rabbit cortical collecting duct. Am J Physiol. 1985 Nov;249(5 Pt 2):F645–F653. doi: 10.1152/ajprenal.1985.249.5.F645. [DOI] [PubMed] [Google Scholar]
  23. Schwartzman M., Ferreri N. R., Carroll M. A., Songu-Mize E., McGiff J. C. Renal cytochrome P450-related arachidonate metabolite inhibits (Na+ + K+)ATPase. Nature. 1985 Apr 18;314(6012):620–622. doi: 10.1038/314620a0. [DOI] [PubMed] [Google Scholar]
  24. Teitelbaum I., Berl T. Effects of calcium on vasopressin-mediated cyclic adenosine monophosphate formation in cultured rat inner medullary collecting tubule cells. Evidence for the role of intracellular calcium. J Clin Invest. 1986 May;77(5):1574–1583. doi: 10.1172/JCI112473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Torikai S., Kurokawa K. Effect of PGE2 on vasopressin-dependent cell cAMP in isolated single nephron segments. Am J Physiol. 1983 Jul;245(1):F58–F66. doi: 10.1152/ajprenal.1983.245.1.F58. [DOI] [PubMed] [Google Scholar]
  26. Toto R., Siddhanta A., Manna S., Pramanik B., Falck J. R., Capdevila J. Arachidonic acid epoxygenase: detection of epoxyeicosatrienoic acids in human urine. Biochim Biophys Acta. 1987 Jun 2;919(2):132–139. doi: 10.1016/0005-2760(87)90199-8. [DOI] [PubMed] [Google Scholar]
  27. Watanabe T., Umegaki K., Smith W. L. Association of a solubilized prostaglandin E2 receptor from renal medulla with a pertussis toxin-reactive guanine nucleotide regulatory protein. J Biol Chem. 1986 Oct 15;261(29):13430–13437. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES