Skip to main content
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1995 Nov;116(5):2401–2406. doi: 10.1111/j.1476-5381.1995.tb15086.x

Failure of the putative neuropeptide Y antagonists, benextramine and PYX-2, to inhibit Y2 receptors in rat isolated prostatic vas deferens.

S Palea 1, M Corsi 1, J M Rimland 1, D G Trist 1, E Ratti 1
PMCID: PMC1909051  PMID: 8581275

Abstract

1. The pharmacological activity of neuropeptide Y (NPY) and some analogues in inhibiting the twitch contractions induced by electrical stimulation (single pulses at 25 V, 0.15 Hz, 1 ms) in the prostatic portion of the rat isolated vas deferens was investigated. The rank order of agonist potency was: PYY > NPY2-36 > NPY >> NPY13-36 >> NPY18-36 >> [Leu31,Pro34]NPY = hPP, which is consistent with the activation of a Y2 receptor. 2. The putative Y1 and Y2 antagonist, benextramine (BXT), incubated at 100 microM for 10 or 60 min, was ineffective against PYY-induced inhibition of the twitch response, suggesting that the prejunctional Y2 receptor in this tissue is different from the postjunctional one reported in the literature to be sensitive to BXT blockade. 3. The putative NPY antagonist, PYX-2, incubated at 1 microM for 20 min, was completely ineffective in antagonizing PYY-induced inhibition of twitches. 4. The twitch response was totally inhibited by suramin (100 microM) but was little affected by prazosin (1 microM). Furthermore, NPY was without effect on the dose-response curve to ATP in resting conditions. Taken together, these results suggest that in our paradigm, NPY inhibits the release of a purinergic neurotransmitter which mediates contraction of the prostatic portion of the rat vas deferens.

Full text

PDF
2401

Selected References

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

  1. Adrian T. E., Gu J., Allen J. M., Tatemoto K., Polak J. M., Bloom S. R. Neuropeptide Y in the human male genital tract. Life Sci. 1984 Dec 24;35(26):2643–2648. doi: 10.1016/0024-3205(84)90033-x. [DOI] [PubMed] [Google Scholar]
  2. Beck B., Stricker-Krongrad A., Musse N., Nicolas J. P., Burlet C. Putative neuropeptide Y antagonist failed to decrease overeating in obese Zucker rats. Neurosci Lett. 1994 Nov 7;181(1-2):126–128. doi: 10.1016/0304-3940(94)90575-4. [DOI] [PubMed] [Google Scholar]
  3. Brown C. M., McGrath J. C., Summers R. J. The effects of alpha-adrenoceptor agonists and antagonists on responses of transmurally stimulated prostatic and epididymal portions of the isolated vas deferens of the rat. Br J Pharmacol. 1979 Aug;66(4):553–564. doi: 10.1111/j.1476-5381.1979.tb13694.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bültmann R., Starke K. P2-purinoceptor antagonists discriminate three contraction-mediating receptors for ATP in rat vas deferens. Naunyn Schmiedebergs Arch Pharmacol. 1994 Jan;349(1):74–80. doi: 10.1007/BF00178209. [DOI] [PubMed] [Google Scholar]
  5. Coppes R. P., Smit J., Geurtsen A. M., Roffel A. F., Dahlöf C., Doods H. N., Zaagsma J. Heterogeneity of prejunctional neuropeptide Y receptors inhibiting noradrenaline overflow in the portal vein of freely moving rats. Eur J Pharmacol. 1994 Aug 22;261(3):311–316. doi: 10.1016/0014-2999(94)90122-8. [DOI] [PubMed] [Google Scholar]
  6. DeLean A., Munson P. J., Rodbard D. Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol. 1978 Aug;235(2):E97–102. doi: 10.1152/ajpendo.1978.235.2.E97. [DOI] [PubMed] [Google Scholar]
  7. Donoso V., Silva M., St-Pierre S., Huidobro-Toro J. P. Neuropeptide Y (NPY), an endogenous presynaptic modulator of adrenergic neurotransmission in the rat vas deferens: structural and functional studies. Peptides. 1988 May-Jun;9(3):545–553. doi: 10.1016/0196-9781(88)90162-3. [DOI] [PubMed] [Google Scholar]
  8. Doods H. N., Krause J. Different neuropeptide Y receptor subtypes in rat and rabbit vas deferens. Eur J Pharmacol. 1991 Oct 29;204(1):101–103. doi: 10.1016/0014-2999(91)90841-d. [DOI] [PubMed] [Google Scholar]
  9. Doughty M. B., Li K., Hu L., Chu S. S., Tessel R. Benextramine-neuropeptide Y (NPY) binding site interactions: characterization of 3H-NPY binding site heterogeneity in rat brain. Neuropeptides. 1992 Nov;23(3):169–180. doi: 10.1016/0143-4179(92)90119-h. [DOI] [PubMed] [Google Scholar]
  10. Feth F., Rascher W., Michel M. C. Neuropeptide Y (NPY) receptors in HEL cells: comparison of binding and functional parameters for full and partial agonists and a non-peptide antagonist. Br J Pharmacol. 1992 Jan;105(1):71–76. doi: 10.1111/j.1476-5381.1992.tb14212.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fuhlendorff J., Gether U., Aakerlund L., Langeland-Johansen N., Thøgersen H., Melberg S. G., Olsen U. B., Thastrup O., Schwartz T. W. [Leu31, Pro34]neuropeptide Y: a specific Y1 receptor agonist. Proc Natl Acad Sci U S A. 1990 Jan;87(1):182–186. doi: 10.1073/pnas.87.1.182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jørgensen J. C., Fuhlendorff J., Schwartz T. W. Structure-function studies on neuropeptide Y and pancreatic polypeptide--evidence for two PP-fold receptors in vas deferens. Eur J Pharmacol. 1990 Sep 4;186(1):105–114. doi: 10.1016/0014-2999(90)94065-6. [DOI] [PubMed] [Google Scholar]
  13. Leibowitz S. F., Xuereb M., Kim T. Blockade of natural and neuropeptide Y-induced carbohydrate feeding by a receptor antagonist PYX-2. Neuroreport. 1992 Nov;3(11):1023–1026. doi: 10.1097/00001756-199211000-00020. [DOI] [PubMed] [Google Scholar]
  14. Li W., MacDonald R. G., Hexum T. D. Benextramine irreversibly inhibits [125I]neuropeptide Y affinity labeling of the Y2 binding protein in bovine hippocampus. Eur J Pharmacol. 1991 May 25;207(1):89–91. doi: 10.1016/s0922-4106(05)80042-2. [DOI] [PubMed] [Google Scholar]
  15. Lundberg J. M., Stjarne L. Neuropeptide Y (NPY) depresses the secretion of 3H-noradrenaline and the contractile response evoked by field stimulation, in rat vas deferens. Acta Physiol Scand. 1984 Mar;120(3):477–479. doi: 10.1111/j.1748-1716.1984.tb07410.x. [DOI] [PubMed] [Google Scholar]
  16. Mallard N., Marshall R., Sithers A., Spriggs B. Suramin: a selective inhibitor of purinergic neurotransmission in the rat isolated vas deferens. Eur J Pharmacol. 1992 Sep 10;220(1):1–10. doi: 10.1016/0014-2999(92)90004-n. [DOI] [PubMed] [Google Scholar]
  17. McAuley M. A., Westfall T. C. Possible location and function of neuropeptide Y receptor subtypes in the rat mesenteric arterial bed. J Pharmacol Exp Ther. 1992 Jun;261(3):863–868. [PubMed] [Google Scholar]
  18. McGrath J. C. Adrenergic and 'non-adrenergic' components in the contractile response of the vas deferens to a single indirect stimulus. J Physiol. 1978 Oct;283:23–39. doi: 10.1113/jphysiol.1978.sp012486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Melchiorre C., Romualdi P., Bolognesi M. L., Donatini A., Ferri S. Binding profile of benextramine at neuropeptide Y receptor subtypes in rat brain areas. Eur J Pharmacol. 1994 Nov 14;265(1-2):93–98. doi: 10.1016/0014-2999(94)90228-3. [DOI] [PubMed] [Google Scholar]
  20. Melchiorre C., Yong M. S., Benfey B. G., Belleau B. Molecular properties of the adrenergic alpha receptor. 2. Optimum covalent inhibition by two different prototypes of polyamine disulfides. J Med Chem. 1978 Nov;21(11):1126–1132. doi: 10.1021/jm00209a007. [DOI] [PubMed] [Google Scholar]
  21. Michel M. C., Schlicker E., Fink K., Boublik J. H., Göthert M., Willette R. N., Daly R. N., Hieble J. P., Rivier J. E., Motulsky H. J. Distinction of NPY receptors in vitro and in vivo. I. NPY-(18-36) discriminates NPY receptor subtypes in vitro. Am J Physiol. 1990 Jul;259(1 Pt 1):E131–E139. doi: 10.1152/ajpendo.1990.259.1.E131. [DOI] [PubMed] [Google Scholar]
  22. Morris J. L., Sabesan S. Comparison of the NPY receptors mediating vasoconstriction of the guinea-pig uterine artery and thoracic vena cava using a range of NPY analogues. Neuropeptides. 1994 Jan;26(1):21–28. doi: 10.1016/0143-4179(94)90088-4. [DOI] [PubMed] [Google Scholar]
  23. Palea S., Corsi M., Rimland J. M., Trist D. G. Discrimination by benextramine between the NPY-Y1 receptor subtypes present in rabbit isolated vas deferens and saphenous vein. Br J Pharmacol. 1995 May;115(1):3–10. doi: 10.1111/j.1476-5381.1995.tb16311.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Plotek Y., Atlas D. Characterization of benextramine as an irreversible alpha-adrenergic blocker and as a blocker of potassium-activated calcium channels. Eur J Biochem. 1983 Jul 1;133(3):539–544. doi: 10.1111/j.1432-1033.1983.tb07497.x. [DOI] [PubMed] [Google Scholar]
  25. Stanley B. G., Magdalin W., Seirafi A., Nguyen M. M., Leibowitz S. F. Evidence for neuropeptide Y mediation of eating produced by food deprivation and for a variant of the Y1 receptor mediating this peptide's effect. Peptides. 1992 May-Jun;13(3):581–587. doi: 10.1016/0196-9781(92)90093-i. [DOI] [PubMed] [Google Scholar]
  26. Stjärne L., Lundberg J. M., Astrand P. Neuropeptide Y--a cotransmitter with noradrenaline and adenosine 5'-triphosphate in the sympathetic nerves of the mouse vas deferens? A biochemical, physiological and electropharmacological study. Neuroscience. 1986 May;18(1):151–166. doi: 10.1016/0306-4522(86)90184-3. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. 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]
  29. 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]
  30. Walker P., Grouzmann E., Burnier M., Waeber B. The role of neuropeptide Y in cardiovascular regulation. Trends Pharmacol Sci. 1991 Mar;12(3):111–115. doi: 10.1016/0165-6147(91)90518-w. [DOI] [PubMed] [Google Scholar]
  31. Wan C. P., Lau B. H. Neuropeptide Y receptor subtypes. Life Sci. 1995 Feb 17;56(13):1055–1064. doi: 10.1016/0024-3205(95)00041-4. [DOI] [PubMed] [Google Scholar]

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

RESOURCES