Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1992 Apr;105(4):875–880. doi: 10.1111/j.1476-5381.1992.tb09071.x

Characterization of the receptor mediating relaxation to substance P in canine middle cerebral artery: no evidence for involvement of substance P in neurogenically mediated relaxation.

C M Stubbs 1, G J Waldron 1, H E Connor 1, W Feniuk 1
PMCID: PMC1908684  PMID: 1380374

Abstract

1. The aim of this study was to characterize the neurokinin receptor which mediates relaxation of dog isolated middle cerebral artery by the use of selective agonists and antagonists and to establish whether substance P is involved in the neurogenically mediated relaxant response in this vessel. 2. Substance P caused concentration-related, endothelium-dependent relaxations of dog isolated middle cerebral artery, contracted with prostaglandin F2 alpha. The selective NK1 receptor agonists, GR73632 and substance P methyl ester (SPOMe), also caused relaxation with similar maximum effects to those of substance P. GR73632 and SPOMe were approximately 20 times and 6 times less potent respectively than substance P. The selective NK2 and NK3 receptor agonists, GR64349 and senktide, were only weakly active in causing relaxation being at least 425 times and 245 times less potent respectively than substance P. 3. The selective NK1 receptor antagonist, GR82334, was a potent, specific, competitive antagonist of the relaxant effects of substance P. In contrast, the selective NK2 receptor antagonist, R396 (10 microM) had no effect on the response to substance P. 4. Electrical field stimulation of dog isolated middle cerebral artery, contracted with prostaglandin F2 alpha, caused neurogenically mediated, non-adrenergic non-cholinergic (NANC) relaxations. These NANC relaxations were unaffected by endothelium removal, GR82334 (10 microM) or by capsaicin (10 microM) treatment. However, the nitric oxide synthesis inhibitor, L-NG-monomethyl arginine methyl ester (L-NMMA) (100 microM) markedly attenuated the response to electrical stimulation. 5. These results suggest that substance P causes relaxation of dog isolated middle cerebral artery via activation of NK1 receptors. However, substance P does not appear to be involved in NANC neurotransmission.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
875

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. Apperley E., Humphrey P. P., Levy G. P. Receptors for 5-hydroxytryptamine and noradrenaline in rabbit isolated ear artery and aorta. Br J Pharmacol. 1976 Oct;58(2):211–221. doi: 10.1111/j.1476-5381.1976.tb10398.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Connor H. E., Feniuk W. Influence of the endothelium on contractile effects of 5-hydroxytryptamine and selective 5-HT agonists in canine basilar artery. Br J Pharmacol. 1989 Jan;96(1):170–178. doi: 10.1111/j.1476-5381.1989.tb11797.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Demolle D., Boeynaems J. M. Cholera and pertussis toxins amplify prostacyclin synthesis in aortic smooth muscle cells. Br J Pharmacol. 1989 Nov;98(3):717–720. doi: 10.1111/j.1476-5381.1989.tb14597.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Duckles S. P., Buck S. H. Substance P in the cerebral vasculature: depletion by capsaicin suggests a sensory role. Brain Res. 1982 Aug 5;245(1):171–174. doi: 10.1016/0006-8993(82)90355-9. [DOI] [PubMed] [Google Scholar]
  6. Duckles S. P. Effects of capsaicin on vascular smooth muscle. Naunyn Schmiedebergs Arch Pharmacol. 1986 May;333(1):59–64. doi: 10.1007/BF00569661. [DOI] [PubMed] [Google Scholar]
  7. Edvinsson L., Nielsen K. C., Owman C., Sporrong B. Cholinergic mechanisms in pial vessels. Histochemistry, electron microscopy and pharmacology. Z Zellforsch Mikrosk Anat. 1972;134(3):311–325. doi: 10.1007/BF00307168. [DOI] [PubMed] [Google Scholar]
  8. Furness J. B., Papka R. E., Della N. G., Costa M., Eskay R. L. Substance P-like immunoreactivity in nerves associated with the vascular system of guinea-pigs. Neuroscience. 1982 Feb;7(2):447–459. doi: 10.1016/0306-4522(82)90279-2. [DOI] [PubMed] [Google Scholar]
  9. Gaw A. J., Aberdeen J., Humphrey P. P., Wadsworth R. M., Burnstock G. Relaxation of sheep cerebral arteries by vasoactive intestinal polypeptide and neurogenic stimulation: inhibition by L-NG-monomethyl arginine in endothelium-denuded vessels. Br J Pharmacol. 1991 Mar;102(3):567–572. doi: 10.1111/j.1476-5381.1991.tb12213.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Guard S., Watson S. P., Maggio J. E., Too H. P., Watling K. J. Pharmacological analysis of [3H]-senktide binding to NK3 tachykinin receptors in guinea-pig ileum longitudinal muscle-myenteric plexus and cerebral cortex membranes. Br J Pharmacol. 1990 Apr;99(4):767–773. doi: 10.1111/j.1476-5381.1990.tb13004.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hobbs A. J., Gibson A. L-NG-nitro-arginine and its methyl ester are potent inhibitors of non-adrenergic, non-cholinergic transmission in the rat anococcygeus. Br J Pharmacol. 1990 Aug;100(4):749–752. doi: 10.1111/j.1476-5381.1990.tb14086.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lee T. J., Hume W. R., Su C., Bevan J. A. Neurogenic vasodilation of cat cerebral arteries. Circ Res. 1978 Apr;42(4):535–542. doi: 10.1161/01.res.42.4.535. [DOI] [PubMed] [Google Scholar]
  13. Lee T. J., Saito A., Berezin I. Vasoactive intestinal polypeptide-like substance: the potential transmitter for cerebral vasodilation. Science. 1984 May 25;224(4651):898–901. doi: 10.1126/science.6719122. [DOI] [PubMed] [Google Scholar]
  14. Li C. G., Rand M. J. Evidence for a role of nitric oxide in the neurotransmitter system mediating relaxation of the rat anococcygeus muscle. Clin Exp Pharmacol Physiol. 1989 Dec;16(12):933–938. doi: 10.1111/j.1440-1681.1989.tb02404.x. [DOI] [PubMed] [Google Scholar]
  15. Maggi C. A., Patacchini R., Giuliani S., Rovero P., Dion S., Regoli D., Giachetti A., Meli A. Competitive antagonists discriminate between NK2 tachykinin receptor subtypes. Br J Pharmacol. 1990 Jul;100(3):589–592. doi: 10.1111/j.1476-5381.1990.tb15851.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Miyauchi T., Ishikawa T., Sugishita Y., Saito A., Goto K. Effects of capsaicin on nonadrenergic noncholinergic nerves in the guinea pig atria: role of calcitonin gene-related peptide as cardiac neurotransmitter. J Cardiovasc Pharmacol. 1987 Dec;10(6):675–682. doi: 10.1097/00005344-198712000-00011. [DOI] [PubMed] [Google Scholar]
  17. Moncada S., Palmer R. M., Higgs E. A. Biosynthesis of nitric oxide from L-arginine. A pathway for the regulation of cell function and communication. Biochem Pharmacol. 1989 Jun 1;38(11):1709–1715. doi: 10.1016/0006-2952(89)90403-6. [DOI] [PubMed] [Google Scholar]
  18. Nantel F., Rouissi N., Rhaleb N. E., Dion S., Drapeau G., Regoli D. The rabbit jugular vein is a contractile NK-1 receptor system. Eur J Pharmacol. 1990 Apr 25;179(3):457–462. doi: 10.1016/0014-2999(90)90189-d. [DOI] [PubMed] [Google Scholar]
  19. Nielsen K. C., Owman C. Adrenergic innervation of pial arteries related to the circle of Willis in the cat. Brain Res. 1967 Dec;6(4):773–776. doi: 10.1016/0006-8993(67)90134-5. [DOI] [PubMed] [Google Scholar]
  20. Palmer R. M., Ferrige A. G., Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987 Jun 11;327(6122):524–526. doi: 10.1038/327524a0. [DOI] [PubMed] [Google Scholar]
  21. Patacchini R., Astolfi M., Quartara L., Rovero P., Giachetti A., Maggi C. A. Further evidence for the existence of NK2 tachykinin receptor subtypes. Br J Pharmacol. 1991 Sep;104(1):91–96. doi: 10.1111/j.1476-5381.1991.tb12390.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Regoli D., Drapeau G., Dion S., Couture R. New selective agonists for neurokinin receptors: pharmacological tools for receptor characterization. Trends Pharmacol Sci. 1988 Aug;9(8):290–295. doi: 10.1016/0165-6147(88)90013-2. [DOI] [PubMed] [Google Scholar]
  23. Regoli D., Drapeau G., Dion S., D'Orléans-Juste P. Receptors for substance P and related neurokinins. Pharmacology. 1989;38(1):1–15. doi: 10.1159/000138512. [DOI] [PubMed] [Google Scholar]
  24. Saito A., Masaki T., Uchiyama Y., Lee T. J., Goto K. Calcitonin gene-related peptide and vasodilator nerves in large cerebral arteries of cats. J Pharmacol Exp Ther. 1989 Jan;248(1):455–462. [PubMed] [Google Scholar]
  25. Saria A., Gamse R., Petermann J., Fischer J. A., Theodorsson-Norheim E., Lundberg J. M. Simultaneous release of several tachykinins and calcitonin gene-related peptide from rat spinal cord slices. Neurosci Lett. 1986 Jan 30;63(3):310–314. doi: 10.1016/0304-3940(86)90376-9. [DOI] [PubMed] [Google Scholar]
  26. Toda N., Okamura T. Possible role of nitric oxide in transmitting information from vasodilator nerve to cerebroarterial muscle. Biochem Biophys Res Commun. 1990 Jul 16;170(1):308–313. doi: 10.1016/0006-291x(90)91275-w. [DOI] [PubMed] [Google Scholar]
  27. Toda N. Relaxant responses to transmural stimulation and nicotine of dog and monkey cerebral arteries. Am J Physiol. 1982 Aug;243(2):H145–H153. doi: 10.1152/ajpheart.1982.243.2.H145. [DOI] [PubMed] [Google Scholar]
  28. Tucker J. F., Brave S. R., Charalambous L., Hobbs A. J., Gibson A. L-NG-nitro arginine inhibits non-adrenergic, non-cholinergic relaxations of guinea-pig isolated tracheal smooth muscle. Br J Pharmacol. 1990 Aug;100(4):663–664. doi: 10.1111/j.1476-5381.1990.tb14072.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Uddman R., Edvinsson L., Ekman R., Kingman T., McCulloch J. Innervation of the feline cerebral vasculature by nerve fibers containing calcitonin gene-related peptide: trigeminal origin and co-existence with substance P. Neurosci Lett. 1985 Nov 20;62(1):131–136. doi: 10.1016/0304-3940(85)90296-4. [DOI] [PubMed] [Google Scholar]
  30. Uddman R., Edvinsson L. Neuropeptides in the cerebral circulation. Cerebrovasc Brain Metab Rev. 1989 Fall;1(3):230–252. [PubMed] [Google Scholar]
  31. Ueda N., Muramatsu I., Sakakibara Y., Fujiwara M. Noncholinergic, nonadrenergic contraction and substance P in rabbit iris sphincter muscle. Jpn J Pharmacol. 1981 Dec;31(6):1071–1079. doi: 10.1254/jjp.31.1071. [DOI] [PubMed] [Google Scholar]
  32. Watson S. P., Sandberg B. E., Hanley M. R., Iversen L. L. Tissue selectivity of substance P alkyl esters: suggesting multiple receptors. Eur J Pharmacol. 1983 Jan 28;87(1):77–84. doi: 10.1016/0014-2999(83)90052-3. [DOI] [PubMed] [Google Scholar]
  33. Wormser U., Laufer R., Hart Y., Chorev M., Gilon C., Selinger Z. Highly selective agonists for substance P receptor subtypes. EMBO J. 1986 Nov;5(11):2805–2808. doi: 10.1002/j.1460-2075.1986.tb04571.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES