Effects of phosphorothioated neuropeptide Y Y1-receptor antisense oligodeoxynucleotide in conscious rats and in human vessels

Xiang Ying Sun, Xiao He Zhao, David Erlinge, Lars Edvinsson, Bo Fallgren, Claes Wahlestedt, Thomas Hedner

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

1. Metabolically stabilized (phosphorothioate) human and rat NPY Y1 receptor oligodeoxynucleotides (ODNs) complimentary to the rat or human Y1 mRNA were synthesized; [sense (rY1-SODN, 5'-AATTCAACTCTGTTCTCC-3'), antisense (hY1-ASODN, 5'-CCTGGGAAAATAATGTTG-3' and rY1-ASODN, 5'-GGAGAACAGAGTTGAATT-3') and mismatches (hY1-MMODN, 5'-CCTGAGATAATAAGGTTG-3' and rY1-MM 5-CTAGATCAGAGATGAAGT-3')] and used to modulate cardiovascular function in vitro in human vessels as well as in vivo in the rat. 2. The objectives of the experiments were to assess the influence of the NPY Y1 receptor on vasomotor function human resistance arteries in vitro and to investigate the contribution of the NPY receptor system to cardiovascular haemodynamics in vivo. 3. Human subcutaneous resistance arteries removed from patients who underwent surgery for non-vascular diseases were incubated in vitro with the stabilized phosphorothioated hY1-receptor ASODN or MMODN (10-7 to 10-5 M). 4. In human resistance vessels preincubated with hY1-AS (10-7 to 10-5 M), the contractile response to NPY was significantly reduced in a dose-dependent fashion. No effects were observed in the hY1-MMODN-incubated vessels at lower concentrations (10-7 M to 10-6 M). 5. The haemodynamic effects of the phosphorothioated rY1-ASODN, SODN or MMODN were investigated in conscious rats during 48 h of continuous infusions. The continuous infusion with the rY1-ASODN did not change MAP while the rY1-SODN unexpectedly induced an early (10-20 h) increase in ambulatory MAP and the rY1-MMODN a late (24-44 h) increase. 6. Contractile responses to NPY (2, 4, 8, 16 and 32 μg kg-1) were significantly reduced in the rats treated with long-term infusion of rY1-ASODN (2.1 mg kg-1 h-1, i.v. infusion for 48 h) compared with animals treated with rY1-SODN and MMODN, as well as animals treated with saline and glucose. Notably, the group infused with the rY1-SODN showed an exaggerated response to tested doses of NPY. 7. We conclude that the incubation of human subcutaneous arteries with a metabolically stabilized 18 base pair hY1-ASODN and long-term infusion with a corresponding rY1-ASODN attenuate NPY-induced vasoconstriction.

Original languageEnglish (US)
Pages (from-to)131-136
Number of pages6
JournalBritish Journal of Pharmacology
Volume118
Issue number1
DOIs
StatePublished - Jan 1 1996
Externally publishedYes

    Fingerprint

Keywords

  • Antisense oligodeoxynucleotide
  • Conscious rat
  • Human artery
  • Long-term infusion
  • Phosphorothioate (metabolically stabilized)

ASJC Scopus subject areas

  • Pharmacology

Cite this