Dopamine D1 receptor-dependent inhibition of NaCl transport in the rat thick ascending limb: Mechanism of action

Jay S. Grider, Cobern E. Ott, Brian A. Jackson

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Our previous in vitro microperfusion studies established that dopamine inhibits sodium chloride transport in the rat medullary thick ascending limb. The present study was designed to determine the intracellular signaling pathway mediating this response. The dopamine D1 receptor agonist fenoldopam (1 μM) inhibited sodium chloride transport in the thick ascending limb by 42±5%. The dopamine D1 receptor antagonist R-(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine-HCl (SCH-23390) completely blocked this effect of fenoldopam. Suppression of protein kinase A activity using either myristoylated protein kinase inhibitor (PKI) or N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide.2HCl (H-89), as well as suppression of phospholipase C activity using 1-(6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H- pyrrole-2,5-dione (U-73122), had no effect on fenoldopam-dependent inhibition of transport. In contrast, inhibition of phospholipase A2 activity using E-6-(Bromomethylene)tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one (HELSS) significantly attenuated the effect of fenoldopam by 74%. The cytochrome P-450 monooxygenase inhibitor 17-octadecynoic acid (17-ODYA) and the protein kinase C inhibitor staurosporine both significantly attenuated the effects of fenoldopam by 67%. Exposure to 20-Hydroxy-(5Z, 8Z, 11Z, 14Z)-eicosatetraenoic acid (20-HETE) inhibited transport by 31±5%, and this effect was significantly attenuated by 66% in the presence of staurosporine. We propose a signaling pathway in which dopamine activates a calcium-independent phospholipase A2 in the medullary thick ascending limb. Released arachidonic acid is then metabolized to 20-HETE which subsequently increases protein kinase C activity that acts as a final transport effector.

Original languageEnglish
Pages (from-to)185-190
Number of pages6
JournalEuropean Journal of Pharmacology
Volume473
Issue number2-3
DOIs
StatePublished - Jul 25 2003

Bibliographical note

Funding Information:
The authors would like to thank William Titlow and Ben Taylor for their expert technical assistance. This work was supported by funding from the American Heart Association (Ohio Valley Affiliate), the National Institutes of Health and a Merit Award from the Veterans Administration.

Keywords

  • Arachidonic acid
  • Fenoldopam
  • Loop of Henle
  • Microperfusion, in vitro
  • Protein kinase C

ASJC Scopus subject areas

  • Pharmacology

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