Epoxygenase products of arachidonic acid are endogenous constituents of the hypothalamus involved in d2receptor-mediated, dopamine-induced release of somatostatin

Marie Pierre Junier, Fernand Dray, Ian Blair, Jorge Capdevila, Elizabeth Dishman, J R Falck, Sergio R. Ojeda

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

The epoxyeicosatrienoic acids (EETs) were discovered as products of a cyclooxygenase/lipoxygenase-independent, cytochrome P-450 catalyzed metabolism of arachidonic acid (AA) termed the “epoxygenase” pathway. The rat hypothalamus is able to synthesize EETs from exogenous AA, and 5, 6- EET has been found to release the neuropeptide somatostatin (SRIF) from hypothalamic nerve terminals of the median eminence (ME). In the present study, hypothalami from male rats were examined for the presence of endogenous EETs, using chemical, chromatographic, and mass spectral analysis procedures. The samples were initially separated in a C18 Sepralyte column, fractionated on TLC plates, and purified by reverse phase HPLC. Thereafter, they were esterified (pentafluorobenzyl esters) and subjected to negative ion chemical ionization/gas chromatography (GC)/mass spectral (MS) analysis. The GC retention time and the MS fragmentation patterns revealed the presence of a mixture of 8, 9-, 11, 12- and 14, 15-EETs; instability of 5, 6-EET during the isolation protocol precluded its identification. Total hypothalamic EET concentration was estimated to be 120 ng/g wet tissue. The 8, 9-regiosomer released SRIF from ME nerve terminals with an ED50 of 5 x 10-12 M; Dopamine (DA) and the D2receptor agonist PPHT, but not the D1receptor agonist SKF-38393, induced SRIF release from the ME. This effect was blocked by clotrimazole and ketoconazole, two inhibitors of microsomal cytochrome P-450 function and AA epoxygenase in particular. In contrast, the inhibitors failed to affect the increase in SRIF release induced by 8, 9-EET. These results indicate that: 1) in addition to cyclooxygenase and lipoxygenase products, epoxygenase metabolites of AA are endogenous compounds of the hypothalamus, and 2) EETs may mediate the increase in SRIF release from hypothalamic neurons induced by the interaction of DA with D2receptors.

Original languageEnglish (US)
Pages (from-to)1534-1540
Number of pages7
JournalEndocrinology
Volume126
Issue number3
DOIs
StatePublished - Mar 1990

ASJC Scopus subject areas

  • Endocrinology

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