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Effects of phosphorothioated neuropeptide Y Y 1 ‐receptor antisense oligodeoxynucleotide in conscious rats and in human vessels
Author(s) -
Sun Xiang Ying,
Zhao Xiao He,
Erlinge David,
Edvinsson Lars,
Fallgren Bo,
Wahlestedt Claes,
Hedner Thomas
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15375.x
Subject(s) - receptor , neuropeptide , neuropeptide y receptor , neuroscience , endocrinology , chemistry , psychology , biology , medicine
1 . Metabolically stabilized (phosphorothioate) human and rat NPY Y x receptor oligodeoxynucleotides (ODNs) complimentary to the rat or human Y 1 mRNA were synthesized; [sense (rY 1 ‐SODN, 5′‐AATTCAACTCTGTTCTCC‐3′), antisense (hY 1 ‐ASODN, 5′‐CCTGGGAAAATAATGTTG‐3′ and rY 1 ‐ASODN, 5′‐GGAGAACAGAGTTGAATT‐3′) and mismatches (hY 1 ‐MMODN, 5′‐CCTG A GA T AA‐TAA G GTTG‐3′ and rY 1 ‐MM 5′‐G T AGA T CAGAG A TGAA G T‐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 Y 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 . 3 . Human subcutaneous resistance arteries removed from patients who underwent surgery for non‐vascular diseases were incubated in vitro with the stabilized phosphorothioated hY 1 ‐receptor ASODN or MMODN (10 −7 to 10 −5 m ). 4 . In human resistance vessels preincubated with hY 1 ‐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 hY 1 ‐MMODN‐incubated vessels at lower concentrations (10 −7 m to 10 −6 m ). 5 . The haemodynamic effects of the phosphorothioated rY 1 ‐ASODN, SODN or MMODN were investigated in conscious rats during 48 h of continuous infusions. The continuous infusion with the rY 1 ‐ASODN did not change MAP while the rY 1 ‐SODN unexpectedly induced an early (10–20 h) increase in ambulatory MAP and the rY 1 ‐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 rY 1 ‐ASODN (2.1 mg kg −1 h −1 , i.v. infusion for 48 h) compared with animals treated with rY 1 ‐SODN and MMODN, as well as animals treated with saline and glucose. Notably, the group infused with the rY 1 ‐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 rY 1 ‐ASODN attenuate NPY‐induced vasoconstriction.