Vasoconstrictor effects of various neuropeptide Y analogues on the rat tail artery in the presence of phenylephrine.
1. The increase in perfusion pressure induced by neuropeptide Y (NPY), peptide YY (PYY) and related peptides were compared in the perfused rat tail artery precontracted by a submaximal concentration (1 microM) of the vasoconstrictor, phenylephrine. 2. NPY, PYY, [Leu31,Pro34]NPY, [Glu16,Ser18,Ala22,Leu28,31]NPY (ESALL-NPY) and the centrally truncated and stabilized analogues [D-Cys5,8-aminooctanoic acid7-20, Cys24]-NPY (D-Cys5-NPY) and [D-Cys7, 8-aminooctanoic acid8-17,Cys20]-NPY (D-Cys7-NPY) produced a concentration-dependent enhancement of the vasoconstrictor response induced by 1 microM phenylephrine. PYY was two times more potent than NPY and [Leu31,Pro34]NPY while ESALL-NPY, D-Cys7-NPY and D-Cys5-NPY were approximately 3, 5 and 16 times less potent than NPY respectively. NPY, D-Cys5-NPY and D-Cys7-NPY gave similar maximal responses whereas those observed for PYY, [Leu31,Pro34]NPY and ESALL-NPY were much greater than that of NPY. 3. NPY 13-36 and [des-Ser3,Lys4,Cys2,8-aminooctanoic acid3-24, D-Cys27]-NPY ([es-Ser3,Lys4]Cys2-NPY) were practically inactive at concentrations up to 3 microM, whereas [des-Ser3,Lys4,D-Cys2,8-aminooctanoic acid3-24,Cys27]-NPY ([des-Ser3,Lys4]D-Cys2-NPY), which differs from [des-Ser3,Lys4]Cys2-NPY in the disulphide bridge (a D-Cys in position 2 for [des-Ser3,Lys4]D-Cys2-NPY instead of an L-CYs for [des-Ser3,Lys4]Cys2-NPY) was a weak agonist the maximal effect of which could not be ascertained. 4. The contractile effects of [des-Ser3,Lys4]D-Cys2-NPY were additive with those of NPY and [Leu31,Pro34]NPY demonstrating that it is not a partial agonist but may simply not interact competitively with the receptor binding site for NPY. NPY and PYY interacted in a manner expected of agonists competing for the same binding site.5. PYY, NPY and [Leu31,Pro34]NPY were equipotent in displacing the I125-labelled PYY from binding sites on membranes from Y1-receptor expressing SK-N-MC cells, while the centrally truncated analogues were much less potent. The rank order of potencies for displacement of the I125-PYY binding by these peptides in SK-N-MC cells correlated with their activity in enhancing the vasoconstrictor response of phenylephrine in the tail artery. For the [des-Ser3,Lys4]D-Cys2-NPY analogue, the displacement pattern was more complex in that the displacement analysis revealed the presence of two binding sites.6. In conclusion, these data provide no evidence for other than postjunctional Y1-receptors mediating the enhancement of the contractile response elicited by phenylephrine in the perfused rat tail artery. The effects of [des-Ser3,Lys4]D-Cys2-NPY indicate that the Y1-receptor may possess an allosteric binding site.
Tschöpl
M
M
Laboratoire de Pharmacologie Cellulaire et Moléculaire, C.N.R.S. URA 600, Université Louis Pasteur Strasbourg, Illkirch, France.
Miller
R C
RC
Pelton
J
J
Stoclet
J C
JC
Bucher
B
B
D000595:Amino Acid Sequence; D000818:Animals; D001158:Arteries / Q000187:drug effects; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D004347:Drug Interactions; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009447:Neuroblastoma; D009478:Neuropeptide Y / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D017476:Receptors, Neuropeptide Y / Q000187:drug effects / Q000502:physiology; D013623:Tail / Q000098:blood supply*; D014407:Tumor Cells, Cultured; D014662:Vasoconstrictor Agents / Q000378:metabolism / Q000494:pharmacology*
D007457:Iodine Radioisotopes; D009478:Neuropeptide Y; D010446:Peptide Fragments; D011942:Receptors, Adrenergic, alpha; D017476:Receptors, Neuropeptide Y; D014662:Vasoconstrictor Agents; C062924:neuropeptide Y (13-36); C062259:neuropeptide Y, Leu(31)-Pro(34)-; D010656:Phenylephrine