Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1995 Oct;116(4):2245–2250. doi: 10.1111/j.1476-5381.1995.tb15060.x

Characterization of neuropeptide Y (NPY) receptors in human cerebral arteries with selective agonists and the new Y1 antagonist BIBP 3226.

R Abounader 1, J G Villemure 1, E Hamel 1
PMCID: PMC1908978  PMID: 8564255

Abstract

1. We have characterized pharmacologically the receptor subtype(s) responsible for the neuropeptide Y (NPY)-induced vasoconstriction in human cerebral arteries. NPY, PYY and several of their derivatives with well defined affinities at the known Y1 and Y2 receptor subtypes were used. Moreover, we tested the ability of the new Y1 receptor antagonist, BIBP 3226, to antagonize the NPY-induced cerebral vasoconstriction. 2. NPY, PYY and their agonists with high affinities at the Y1 receptor subtype ([Leu31-Pro34]-NPY and [Leu31-Pro34]-PYY) elicited strong, long lasting and concentration-dependent contractions of human cerebral arteries. Compounds with Y2 affinity such as PYY3-36 or NPY13-36 either elicited a submaximal contraction at high concentrations or failed to induce any significant vasomotor response. Also, the application of NPY or the specific Y1 agonist, [Leu31-Pro34]-NPY, to human cerebral vessels pretreated with the Y1 agonist, NPY13-36, resulted in contractile responses identical to those obtained when these compounds were tested without prior application of NPY13-36. 3. The order of agonist potency at the human cerebrovascular receptor was: [Leu31-Pro34]-NPY = [Leu31-Pro34]-PYY > or = NPY > PYY > PYY3-36 > > > NPY13-36, which corresponded to that reported previously at the neuronal and vascular Y1 receptors. 4. Increasing concentrations (10(-9)-10(-6) M) of the Y1 receptor antagonist, BIBP 3226, to human cerebral vessels caused a parallel and rightward shift in the NPY dose-response curves without any significant change in the maximal contractile response.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
2245

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ARUNLAKSHANA O., SCHILD H. O. Some quantitative uses of drug antagonists. Br J Pharmacol Chemother. 1959 Mar;14(1):48–58. doi: 10.1111/j.1476-5381.1959.tb00928.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Adrian T. E., Allen J. M., Bloom S. R., Ghatei M. A., Rossor M. N., Roberts G. W., Crow T. J., Tatemoto K., Polak J. M. Neuropeptide Y distribution in human brain. Nature. 1983 Dec 8;306(5943):584–586. doi: 10.1038/306584a0. [DOI] [PubMed] [Google Scholar]
  3. Cadieux A., Pheng L. H., St-Pierre S., Fournier A., Benchekroun M. T. The rabbit saphenous vein: a tissue preparation specifically enriched in NPY-Y1 receptor subtype. Regul Pept. 1993 Jul 23;46(3):557–564. doi: 10.1016/0167-0115(93)90257-9. [DOI] [PubMed] [Google Scholar]
  4. Dacey R. G., Jr, Bassett J. E., Takayasu M. Vasomotor responses of rat intracerebral arterioles to vasoactive intestinal peptide, substance P, neuropeptide Y, and bradykinin. J Cereb Blood Flow Metab. 1988 Apr;8(2):254–261. doi: 10.1038/jcbfm.1988.56. [DOI] [PubMed] [Google Scholar]
  5. Doughty M. B., Chu S. S., Miller D. W., Li K., Tessel R. E. Benextramine: a long-lasting neuropeptide Y receptor antagonist. Eur J Pharmacol. 1990 Aug 21;185(1):113–114. doi: 10.1016/0014-2999(90)90218-u. [DOI] [PubMed] [Google Scholar]
  6. Dumont Y., Cadieux A., Pheng L. H., Fournier A., St-Pierre S., Quirion R. Peptide YY derivatives as selective neuropeptide Y/peptide YY Y1 and Y2 agonists devoided of activity for the Y3 receptor sub-type. Brain Res Mol Brain Res. 1994 Oct;26(1-2):320–324. doi: 10.1016/0169-328x(94)90105-8. [DOI] [PubMed] [Google Scholar]
  7. Dumont Y., Fournier A., St-Pierre S., Quirion R. Comparative characterization and autoradiographic distribution of neuropeptide Y receptor subtypes in the rat brain. J Neurosci. 1993 Jan;13(1):73–86. doi: 10.1523/JNEUROSCI.13-01-00073.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Edvinsson L., Ekman R., Jansen I., Ottosson A., Uddman R. Peptide-containing nerve fibers in human cerebral arteries: immunocytochemistry, radioimmunoassay, and in vitro pharmacology. Ann Neurol. 1987 May;21(5):431–437. doi: 10.1002/ana.410210503. [DOI] [PubMed] [Google Scholar]
  9. Edvinsson L., Emson P., McCulloch J., Tatemoto K., Uddman R. Neuropeptide Y: cerebrovascular innervation and vasomotor effects in the cat. Neurosci Lett. 1983 Dec 23;43(1):79–84. doi: 10.1016/0304-3940(83)90132-5. [DOI] [PubMed] [Google Scholar]
  10. Edvinsson L., Erlinge D., Sun X. Y., Hedner T. Neuropeptide Y in sympathetic co-transmission: recent advances in the search for neuropeptide Y antagonists. Pharmacol Toxicol. 1994 Apr-May;74(4-5):193–201. doi: 10.1111/j.1600-0773.1994.tb01098.x. [DOI] [PubMed] [Google Scholar]
  11. Ekblad E., Edvinsson L., Wahlestedt C., Uddman R., Håkanson R., Sundler F. Neuropeptide Y co-exists and co-operates with noradrenaline in perivascular nerve fibers. Regul Pept. 1984 Apr;8(3):225–235. doi: 10.1016/0167-0115(84)90064-8. [DOI] [PubMed] [Google Scholar]
  12. Erlinge D., Edvinsson L., Brunkwall J., Yee F., Wahlestedt C. Human neuropeptide Y Y1 receptor antisense oligodeoxynucleotide specifically inhibits neuropeptide Y-evoked vasoconstriction. Eur J Pharmacol. 1993 Aug 10;240(1):77–80. doi: 10.1016/0014-2999(93)90548-v. [DOI] [PubMed] [Google Scholar]
  13. Grandt D., Schimiczek M., Struk K., Shively J., Eysselein V. E., Goebell H., Reeve J. R., Jr Characterization of two forms of peptide YY, PYY(1-36) and PYY(3-36), in the rabbit. Peptides. 1994;15(5):815–820. doi: 10.1016/0196-9781(94)90035-3. [DOI] [PubMed] [Google Scholar]
  14. Grundemar L., Håkanson R. Multiple neuropeptide Y receptors are involved in cardiovascular regulation. Peripheral and central mechanisms. Gen Pharmacol. 1993 Jul;24(4):785–796. doi: 10.1016/0306-3623(93)90151-m. [DOI] [PubMed] [Google Scholar]
  15. Grundemar L., Jonas S. E., Mörner N., Högestätt E. D., Wahlestedt C., Håkanson R. Characterization of vascular neuropeptide Y receptors. Br J Pharmacol. 1992 Jan;105(1):45–50. doi: 10.1111/j.1476-5381.1992.tb14208.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Grundemar L., Wahlestedt C., Reis D. J. Neuropeptide Y acts at an atypical receptor to evoke cardiovascular depression and to inhibit glutamate responsiveness in the brainstem. J Pharmacol Exp Ther. 1991 Aug;258(2):633–638. [PubMed] [Google Scholar]
  17. Hamel E., Bouchard D. Contractile 5-HT1 receptors in human isolated pial arterioles: correlation with 5-HT1D binding sites. Br J Pharmacol. 1991 Jan;102(1):227–233. doi: 10.1111/j.1476-5381.1991.tb12158.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hamel E., Grégoire L., Lau B. 5-HT1 receptors mediating contraction in bovine cerebral arteries: a model for human cerebrovascular '5-HT1D beta' receptors. Eur J Pharmacol. 1993 Sep 21;242(1):75–82. doi: 10.1016/0014-2999(93)90012-7. [DOI] [PubMed] [Google Scholar]
  19. Herzog H., Hort Y. J., Ball H. J., Hayes G., Shine J., Selbie L. A. Cloned human neuropeptide Y receptor couples to two different second messenger systems. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):5794–5798. doi: 10.1073/pnas.89.13.5794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Högestätt E. D., Andersson K. E., Edvinsson L. Mechanical properties of rat cerebral arteries as studied by a sensitive device for recording of mechanical activity in isolated small blood vessels. Acta Physiol Scand. 1983 Jan;117(1):49–61. doi: 10.1111/j.1748-1716.1983.tb07178.x. [DOI] [PubMed] [Google Scholar]
  21. Krstenansky J. L., Owen T. J., Payne M. H., Shatzer S. A., Buck S. H. C-terminal modifications of neuropeptide Y and its analogs leading to selectivity for the mouse brain receptor over the porcine spleen receptor. Neuropeptides. 1990 Nov;17(3):117–120. doi: 10.1016/0143-4179(90)90073-8. [DOI] [PubMed] [Google Scholar]
  22. Larhammar D., Blomqvist A. G., Yee F., Jazin E., Yoo H., Wahlested C. Cloning and functional expression of a human neuropeptide Y/peptide YY receptor of the Y1 type. J Biol Chem. 1992 Jun 5;267(16):10935–10938. [PubMed] [Google Scholar]
  23. Lundberg J. M., Tatemoto K. Pancreatic polypeptide family (APP, BPP, NPY and PYY) in relation to sympathetic vasoconstriction resistant to alpha-adrenoceptor blockade. Acta Physiol Scand. 1982 Dec;116(4):393–402. doi: 10.1111/j.1748-1716.1982.tb07157.x. [DOI] [PubMed] [Google Scholar]
  24. Lundberg J. M., Terenius L., Hökfelt T., Martling C. R., Tatemoto K., Mutt V., Polak J., Bloom S., Goldstein M. Neuropeptide Y (NPY)-like immunoreactivity in peripheral noradrenergic neurons and effects of NPY on sympathetic function. Acta Physiol Scand. 1982 Dec;116(4):477–480. doi: 10.1111/j.1748-1716.1982.tb07171.x. [DOI] [PubMed] [Google Scholar]
  25. McDermott B. J., Millar B. C., Piper H. M. Cardiovascular effects of neuropeptide Y: receptor interactions and cellular mechanisms. Cardiovasc Res. 1993 Jun;27(6):893–905. doi: 10.1093/cvr/27.6.893. [DOI] [PubMed] [Google Scholar]
  26. Mejia J. A., Pernow J., von Holst H., Rudehill A., Lundberg J. M. Effects of neuropeptide Y, calcitonin gene-related peptide, substance P, and capsaicin on cerebral arteries in man and animals. J Neurosurg. 1988 Dec;69(6):913–918. doi: 10.3171/jns.1988.69.6.0913. [DOI] [PubMed] [Google Scholar]
  27. Michel M. C. Receptors for neuropeptide Y: multiple subtypes and multiple second messengers. Trends Pharmacol Sci. 1991 Oct;12(10):389–394. doi: 10.1016/0165-6147(91)90610-5. [DOI] [PubMed] [Google Scholar]
  28. Mikkelsen J. D., Larsen P. J., Kruse-Larsen C., O'Hare M. M., Schwartz T. W. Immunohistochemical and chromatographic identification of peptides derived from proneuropeptide Y in the human frontal cortex. Brain Res Bull. 1993;31(3-4):415–425. doi: 10.1016/0361-9230(93)90235-4. [DOI] [PubMed] [Google Scholar]
  29. Rudolf K., Eberlein W., Engel W., Wieland H. A., Willim K. D., Entzeroth M., Wienen W., Beck-Sickinger A. G., Doods H. N. The first highly potent and selective non-peptide neuropeptide Y Y1 receptor antagonist: BIBP3226. Eur J Pharmacol. 1994 Dec 27;271(2-3):R11–R13. doi: 10.1016/0014-2999(94)90822-2. [DOI] [PubMed] [Google Scholar]
  30. Sheikh S. P., Roach E., Fuhlendorff J., Williams J. A. Localization of Y1 receptors for NPY and PYY on vascular smooth muscle cells in rat pancreas. Am J Physiol. 1991 Feb;260(2 Pt 1):G250–G257. doi: 10.1152/ajpgi.1991.260.2.G250. [DOI] [PubMed] [Google Scholar]
  31. Shigeri Y., Mihara S., Fujimoto M. Neuropeptide Y receptor in vascular smooth muscle. J Neurochem. 1991 Mar;56(3):852–859. doi: 10.1111/j.1471-4159.1991.tb02001.x. [DOI] [PubMed] [Google Scholar]
  32. Tatemoto K., Mann M. J., Shimizu M. Synthesis of receptor antagonists of neuropeptide Y. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1174–1178. doi: 10.1073/pnas.89.4.1174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Tatemoto K. Neuropeptide Y: complete amino acid sequence of the brain peptide. Proc Natl Acad Sci U S A. 1982 Sep;79(18):5485–5489. doi: 10.1073/pnas.79.18.5485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Tessel R. E., Miller D. W., Misse G. A., Dong X., Doughty M. B. Characterization of vascular postsynaptic neuropeptide Y receptor function and regulation. 1. NPY-induced constriction in isolated rat femoral artery rings is mediated by both Y1 and Y2 receptors: evidence from benextramine protection studies. J Pharmacol Exp Ther. 1993 Apr;265(1):172–177. [PubMed] [Google Scholar]
  35. Wahlestedt C., Grundemar L., Håkanson R., Heilig M., Shen G. H., Zukowska-Grojec Z., Reis D. J. Neuropeptide Y receptor subtypes, Y1 and Y2. Ann N Y Acad Sci. 1990;611:7–26. doi: 10.1111/j.1749-6632.1990.tb48918.x. [DOI] [PubMed] [Google Scholar]
  36. Wahlestedt C., Yanaihara N., Håkanson R. Evidence for different pre-and post-junctional receptors for neuropeptide Y and related peptides. Regul Pept. 1986 Feb;13(3-4):307–318. doi: 10.1016/0167-0115(86)90048-0. [DOI] [PubMed] [Google Scholar]
  37. de Quidt M. E., Emson P. C. Distribution of neuropeptide Y-like immunoreactivity in the rat central nervous system--II. Immunohistochemical analysis. Neuroscience. 1986 Jul;18(3):545–618. doi: 10.1016/0306-4522(86)90057-6. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES