The Nitric Oxide- and Prostaglandin-Independent Component of the Renal Vasodilator Effect of Thimerosal Is Mediated by Epoxyeicosatrienoic Acids
| Autor: | Houli Jiang, John Quilley, Yu-Jung Chen |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Male
Epoxygenase Potassium Channels Vasodilator Agents Prostaglandin Bradykinin Vasodilation Pharmacology Kidney Nitric Oxide Cytochrome P-450 CYP2J2 Nitric oxide Biological Factors chemistry.chemical_compound 8 11 14-Eicosatrienoic Acid Cytochrome P-450 Enzyme System Animals Rats Wistar biology Thimerosal Rats Nitric oxide synthase chemistry Biochemistry Prostaglandin-Endoperoxide Synthases Oxygenases Prostaglandins cardiovascular system biology.protein Molecular Medicine lipids (amino acids peptides and proteins) Arachidonic acid Endothelium Vascular Cyclooxygenase Nitric Oxide Synthase |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 304:1292-1298 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.102.042671 |
| Popis: | Epoxyeicosatrienoic acids (EETs) are cytochrome P450-derived metabolites of arachidonic acid that elicit vasodilation via activation of K(+) channels. They have been implicated as endothelium-derived hyperpolarizing factors (EDHFs), mediating the effect of some endothelium-dependent vasodilator agents such as bradykinin in some vascular tissues. We reasoned that an agent that increases the availability of free arachidonic acid should also elicit cytochrome P450-dependent vasodilation that is associated with increased release of EETs and attenuated by agents that inhibit the synthesis or action of EETs. Thus, we used thimerosal as an inhibitor of reacylation of arachidonic acid and determined the contribution of prostaglandins, nitric oxide, and EETs to the vasodilator effect in the isolated, perfused, preconstricted kidney of the rat. Thimerosal elicited vasodilator responses that were unaffected by inhibition of cyclooxygenase with indomethacin but were reduced by the further inhibition of nitric oxide synthesis. The vasodilator activity that remained after inhibition of cyclooxygenase and nitric oxide synthase was reduced by inhibition of K(+) channels with tetraethylammonium and was associated with increased release of EETs measured by gas chromatography-mass spectroscopy following hydrolysis to the corresponding diols. Inhibition of cytochrome P450 with miconazole or epoxygenase with N-methylsulfonyl-6-(2-propargyloxyphenyl)hexamide reduced the nitric oxide- and prostaglandin-independent vasodilator effect of thimerosal and attenuated the increase in the release of EETs. We conclude that thimerosal causes vasodilation of the isolated perfused kidney via nitric oxide-dependent and -independent mechanisms. The nitric oxide-independent component of the response involves activation of K(+) channels and is likely mediated by EETs, possibly acting as EDHFs. |
| Databáze: | OpenAIRE |
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