Skip to main content
PMC home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1995 Apr;114(8):1680–1686. doi: 10.1111/j.1476-5381.1995.tb14957.x

Vascular actions of thrombin receptor-derived polypeptides: structure-activity profiles for contractile and relaxant effects in rat aorta.

A A Laniyonu 1, M D Hollenberg 1
PMCID: PMC1510399  PMID: 7541284

Abstract

1. Using endothelium-denuded and intact rat aortic rings, we have determined the contractile and relaxant structure-activity profile for a series of thrombin receptor-derived polypeptides (TRPs) based on the human and rat receptor sequences: SFLLR (P5), SFLLR-NH2 (P5-NH2) SFFLR (Rat P5), SFFLR-NH2 (Rat P5-NH2), SFLLRNP (P7), SFLLRNP-NH2 (P7-NH2), SFFLRNP (Rat P7), SFFLRNP-NH2 (Rat P7-NH2), and SFLLRNPNDKYEPF (P14). 2. A contractile response to thrombin and the TRPs in the endothelium-denuded aortic tissue was minimal or absent in preparations obtained from animal weighing less than 180 g (< 6 weeks of age), but increased with animal size, plateauing in tissues derived from animals weighing between 320 and 420 g (about 9 to 14 weeks of age). In contrast, the contractile responses to KCl and noradrenaline did not differ in the tissues and relaxant responses to the TRPs in endothelium-intact aortic preparations were comparable for tissues obtained from either young (< or = 180 g) or older (> or = 320 g) animals. 3. The contractile response of the endothelium-denuded preparation to thrombin and the TRPs showed marked cross-desensitization: the relaxation response of the intact rings did not desensitize to the TRPs. 4. The relative potencies for the TRPs in the aortic contraction assay were comparable to those for the relaxation assay, but were distinct from the relative potencies we measured previously in a rat gastric longitudinal muscle contraction assay. Further, P5 behaved as a partial agonist in the aortic contraction assay, whereas it had been observed to be a full agonist in the gastric contraction assay.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
1681

Selected References

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

  1. Antonaccio M. J., Normandin D., Serafino R., Moreland S. Effects of thrombin and thrombin receptor activating peptides on rat aortic vascular smooth muscle. J Pharmacol Exp Ther. 1993 Jul;266(1):125–132. [PubMed] [Google Scholar]
  2. Chao B. H., Kalkunte S., Maraganore J. M., Stone S. R. Essential groups in synthetic agonist peptides for activation of the platelet thrombin receptor. Biochemistry. 1992 Jul 14;31(27):6175–6178. doi: 10.1021/bi00142a001. [DOI] [PubMed] [Google Scholar]
  3. Coller B. S., Ward P., Ceruso M., Scudder L. E., Springer K., Kutok J., Prestwich G. D. Thrombin receptor activating peptides: importance of the N-terminal serine and its ionization state as judged by pH dependence, nuclear magnetic resonance spectroscopy, and cleavage by aminopeptidase M. Biochemistry. 1992 Dec 1;31(47):11713–11720. doi: 10.1021/bi00162a007. [DOI] [PubMed] [Google Scholar]
  4. Coughlin S. R., Vu T. K., Hung D. T., Wheaton V. I. Characterization of a functional thrombin receptor. Issues and opportunities. J Clin Invest. 1992 Feb;89(2):351–355. doi: 10.1172/JCI115592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. De Mey J. G., Claeys M., Vanhoutte P. M. Endothelium-dependent inhibitory effects of acetylcholine, adenosine triphosphate, thrombin and arachidonic acid in the canine femoral artery. J Pharmacol Exp Ther. 1982 Jul;222(1):166–173. [PubMed] [Google Scholar]
  6. Godin D., Marceau F., Beaulé C., Rioux F., Drapeau G. Aminopeptidase modulation of the pharmacological responses to synthetic thrombin receptor agonists. Eur J Pharmacol. 1994 Mar 3;253(3):225–230. doi: 10.1016/0014-2999(94)90195-3. [DOI] [PubMed] [Google Scholar]
  7. Haver V. M., Namm D. H. Characterization of the thrombin-induced contraction of vascular smooth muscle. Blood Vessels. 1984;21(2):53–63. [PubMed] [Google Scholar]
  8. Hollenberg M. D., Laniyonu A. A., Saifeddine M., Moore G. J. Role of the amino- and carboxyl-terminal domains of thrombin receptor-derived polypeptides in biological activity in vascular endothelium and gastric smooth muscle: evidence for receptor subtypes. Mol Pharmacol. 1993 Jun;43(6):921–930. [PubMed] [Google Scholar]
  9. Hollenberg M. D., Yang S. G., Laniyonu A. A., Moore G. J., Saifeddine M. Action of thrombin receptor polypeptide in gastric smooth muscle: identification of a core pentapeptide retaining full thrombin-mimetic intrinsic activity. Mol Pharmacol. 1992 Aug;42(2):186–191. [PubMed] [Google Scholar]
  10. Hui K. Y., Jakubowski J. A., Wyss V. L., Angleton E. L. Minimal sequence requirement of thrombin receptor agonist peptide. Biochem Biophys Res Commun. 1992 Apr 30;184(2):790–796. doi: 10.1016/0006-291x(92)90659-9. [DOI] [PubMed] [Google Scholar]
  11. Kenakin T. P., Morgan P. H. Theoretical effects of single and multiple transducer receptor coupling proteins on estimates of the relative potency of agonists. Mol Pharmacol. 1989 Feb;35(2):214–222. [PubMed] [Google Scholar]
  12. Muramatsu I., Laniyonu A., Moore G. J., Hollenberg M. D. Vascular actions of thrombin receptor peptide. Can J Physiol Pharmacol. 1992 Jul;70(7):996–1003. doi: 10.1139/y92-137. [DOI] [PubMed] [Google Scholar]
  13. Rapoport R. M., Draznin M. B., Murad F. Mechanisms of adenosine triphosphate-, thrombin-, and trypsin-induced relaxation of rat thoracic aorta. Circ Res. 1984 Oct;55(4):468–479. doi: 10.1161/01.res.55.4.468. [DOI] [PubMed] [Google Scholar]
  14. Rasmussen U. B., Vouret-Craviari V., Jallat S., Schlesinger Y., Pagès G., Pavirani A., Lecocq J. P., Pouysségur J., Van Obberghen-Schilling E. cDNA cloning and expression of a hamster alpha-thrombin receptor coupled to Ca2+ mobilization. FEBS Lett. 1991 Aug 19;288(1-2):123–128. doi: 10.1016/0014-5793(91)81017-3. [DOI] [PubMed] [Google Scholar]
  15. Sabo T., Gurwitz D., Motola L., Brodt P., Barak R., Elhanaty E. Structure-activity studies of the thrombin receptor activating peptide. Biochem Biophys Res Commun. 1992 Oct 30;188(2):604–610. doi: 10.1016/0006-291x(92)91099-c. [DOI] [PubMed] [Google Scholar]
  16. Vassallo R. R., Jr, Kieber-Emmons T., Cichowski K., Brass L. F. Structure-function relationships in the activation of platelet thrombin receptors by receptor-derived peptides. J Biol Chem. 1992 Mar 25;267(9):6081–6085. [PubMed] [Google Scholar]
  17. Vu T. K., Hung D. T., Wheaton V. I., Coughlin S. R. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell. 1991 Mar 22;64(6):1057–1068. doi: 10.1016/0092-8674(91)90261-v. [DOI] [PubMed] [Google Scholar]
  18. Walz D. A., Anderson G. F., Ciaglowski R. E., Aiken M., Fenton J. W., 2nd Thrombin-elicited contractile responses of aortic smooth muscle. Proc Soc Exp Biol Med. 1985 Dec;180(3):518–526. doi: 10.3181/00379727-180-42211. [DOI] [PubMed] [Google Scholar]
  19. Walz D. A., Anderson G. F., Fenton J. W., 2nd Responses of aortic smooth muscle to thrombin and thrombin analogues. Ann N Y Acad Sci. 1986;485:323–334. doi: 10.1111/j.1749-6632.1986.tb34594.x. [DOI] [PubMed] [Google Scholar]
  20. White R. P., Chapleau C. E., Dugdale M., Robertson J. T. Cerebral arterial contractions induced by human and bovine thrombin. Stroke. 1980 Jul-Aug;11(4):363–368. doi: 10.1161/01.str.11.4.363. [DOI] [PubMed] [Google Scholar]
  21. White R. P., Shirasawa Y., Robertson J. T. Comparison of responses elicited by alpha-thrombin in isolated canine basilar, coronary, mesenteric, and renal arteries. Blood Vessels. 1984;21(1):12–22. doi: 10.1159/000158490. [DOI] [PubMed] [Google Scholar]
  22. Yang S. G., Laniyonu A., Saifeddine M., Moore G. J., Hollenberg M. D. Actions of thrombin and thrombin receptor peptide analogues in gastric and aortic smooth muscle: development of bioassays for structure-activity studies. Life Sci. 1992;51(17):1325–1332. doi: 10.1016/0024-3205(92)90631-x. [DOI] [PubMed] [Google Scholar]
  23. deBlois D., Drapeau G., Petitclerc E., Marceau F. Synergism between the contractile effect of epidermal growth factor and that of des-Arg9-bradykinin or of alpha-thrombin in rabbit aortic rings. Br J Pharmacol. 1992 Apr;105(4):959–967. doi: 10.1111/j.1476-5381.1992.tb09085.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES