Effects of phosphorothioated neuropeptide Y Y sub(1)-receptor antisense oligodeoxynucleotide in conscious rats and in human vessels

• Published in: British journal of pharmacology Vol. 118; no. 1; pp. 131 - 136
• Main Authors: Sun, Xiang Ying, Zhao, Xiao He, Erlinge, D, Edvinsson, L, Fallgren, B, Wahlestedt, C, Hedner, T
• Format: Journal Article
• Language: English
• Published: 01-01-1996
• ISSN: 0007-1188

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