Endothelin-1 and nitric oxide affect human cerebromicrovascular endothelial responses and signal transduction

Acta Neurochir Suppl. 2000;76:131-5. doi: 10.1007/978-3-7091-6346-7_27.

Abstract

Endothelium plays a central role in regulating the vascular tone, blood flow and blood brain barrier (BBB) permeability. The experiments presented here examine the mechanisms by which nitric oxide (NO) and endothelin-1 (ET-1) may be involved in these processes. The findings indicate that ET-1-stimulated [Ca2+]i accumulation occurs through activation of ETA receptor. The capacity of NO to affect this response was indicated by results showing: 1) a two-fold increase in ET-1-stimulated [Ca2+]i by L-NAME, the inhibitor of nitric oxide synthase, and 2) a dose-dependent decrease in [Ca2+]i accumulation by pretreatment with Nor-1 (NO donor). Abrogation of this Nor-1 effect by ODQ (an inhibitor of guanylyl cyclase) or Rp-8-pCPT-cGMPS (an inhibitor of protein kinase G) and inhibition of ET-1 stimulated intracellular Ca2+ accumulation by 8-bromo-cGMP (a permeable, analog of cGMP) substantiate the involvement of interplay between ET-1 and NO in [Ca2+]i accumulation in HBMEC. ET-1 treatment also increased thickness of F-actin cytoskeletal filaments in HBMEC. This effect was attenuated by pretreatment with NO; NO also rarefied F-actin filaments in control cultures. The findings support a linkage between NO and ET-1 in regulating microvascular tone, microcirculation and BBB permeability and indicate a role for cGMP/cGMP protein kinase system and cytoskeletal changes in responses of HBMEC.

MeSH terms

  • Actins / physiology
  • Blood-Brain Barrier / physiology*
  • Brain / blood supply*
  • Brain Edema / physiopathology*
  • Calcium / metabolism
  • Capillary Permeability / physiology
  • Cells, Cultured
  • Endothelin-1 / physiology*
  • Endothelium, Vascular / physiopathology*
  • Humans
  • Microcirculation / physiopathology
  • Nitric Oxide / physiology*
  • Signal Transduction / physiology*

Substances

  • Actins
  • Endothelin-1
  • Nitric Oxide
  • Calcium