Endothelin-1 inhibits nitric oxide synthesis in vascular smooth muscle cells

Hypertension. 1997 Jan;29(1 Pt 1):65-9. doi: 10.1161/01.hyp.29.1.65.


We investigated the effects of endothelin-1 on nitric oxide synthesis in vascular smooth muscle cells. We measured the production of nitrite, a stable metabolite of nitric oxide, and the expression of inducible nitric oxide synthase mRNA and protein in cultured rat vascular smooth muscle cells. Incubation of the cultures with interleukin-1 beta (10 ng/mL) for 24 hours caused a significant increase in nitrite production. Endothelin-1 significantly decreased the interleukin-1 beta-induced nitrite production by vascular smooth muscle cells in a dose-dependent manner (10(-11) to 10(-8) mol/L). Incubation with interleukin-1 beta for 24 hours induced expression of inducible nitric oxide synthase mRNA and protein in vascular smooth muscle cells, whereas endothelin-1 showed a suppressive effect on their expressions. Addition of the endothelin type A receptor antagonist BQ-485, but not the endothelin type B receptor antagonist BQ-788, dose-dependently inhibited the effect of endothelin-1. After protein kinase C activity was functionally depleted by treatment of cells with phorbol 12-myristate 13-acetate for 24 hours, the effect of endothelin-1 was abolished. These results indicate that endothelin-1 acts on endothelin type A receptors and inhibits nitric oxide synthesis in interleukin-1 beta-stimulated vascular smooth muscle cells at least partially through a protein kinase C-dependent pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azepines / pharmacology
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Endothelin Receptor Antagonists
  • Endothelin-1 / pharmacology*
  • Gene Expression Regulation, Enzymologic
  • Interleukin-1 / pharmacology
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism*
  • Nitric Oxide / biosynthesis*
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / metabolism
  • Oligopeptides / pharmacology
  • Piperidines / pharmacology
  • Protein Kinase C / metabolism
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Endothelin / metabolism
  • Time Factors


  • Azepines
  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Interleukin-1
  • Oligopeptides
  • Piperidines
  • RNA, Messenger
  • Receptors, Endothelin
  • BQ 485
  • Nitric Oxide
  • BQ 788
  • Nitric Oxide Synthase
  • Protein Kinase C