HUMAN NEUROPEPTIDE-Y Y(1)-RECEPTOR ANTISENSE OLIGODEOXYNUCLEOTIDE SPECIFICALLY INHIBITS NEUROPEPTIDE Y-EVOKED VASOCONSTRICTION

This paper describes a new approach for the development of an inhibito r of the contractile responses of neuropeptide Y in human blood vessel s by the use of an antisense oligodeoxynucleotide complementary to hum an neuropeptide Y Y1 receptor mRNA. One micromolar of an antisense 18- base oligodeoxynucleotide (hY1-AS), corresponding to the human Y1 rece ptor NH2-terminus, was incubated with segments of human subcutaneous a rteries and veins for 48 h at 37-degrees-C. Control vessels were incub ated with the corresponding sense oligodeoxynucleotide (hY1-S) or a 3- base mismatched antisense oligodeoxynucleotide (hY1-MM) or no oligodeo xynucleotide. The contractile response to neuropeptide Y was markedly attenuated in both arteries and veins after treatment with hY1-AS, but was unaffected by hY1-S or hY1-MM. The pD2 values, i.e. the potency o f neuropeptide Y, did not differ in hY1-AS treated vessels, suggesting a non-competitive receptor interaction as a result of down-regulation of Y1 receptors. Responses to noradrenaline or high K+ were unaffecte d by hY1-AS. This study may represent a new and highly specific approa ch to vascular pharmacology.