Skip to main content
SpringerLink
Log in

Effects of endothelin receptor antagonists on bradykinin-induced increases in macromolecular efflux

  • Original Articles
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

The goal of this study was to determine the effects of endothelin receptor antagonists on agonist-induced increases in macromolecular extravasation in the hamster cheek pouch in vivo. We used intravital fluorescent microscopy and fluorescein isothiocyanate dextran (FITC-dextran; mol wt=70 K) to examine extravasation from postcapillary venules in response to bradykinin and endothelin before and following application of inhibitors of endothelin receptors (ETABand ETA). Increases in extravasation of macromolecules were quantitated by counting the number of venular leaky sites. Bradykinin (0.5 and 1.0μM) and endothelin-1 (0.01 and 0.1 nM) produced a dose-related increase in the number of venular leaky sites and superfusion of PD 142893 (ETABantagonist), and PD 147953 and BQ-123 (ETAantagonists) significantly decreased bradykinin- and endothelin-induced responses. Addition of calcium to the superfusate restored bradykinin-induced increases in venular leaky sites in the presence of endothelin receptor antagonism. Thus, the findings of the present study suggest that endothelin receptor antagonists abrogate bradykinin- and endothelin-induced increases in macromolecular efflux from postcapillary venules. The mechanism for the effects of endothelin receptor antagonists appears to be related to inhibition of the ETAreceptor which, in turn, alters the mobilization of calcium across venular endothelium.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Furchgott, R. F., andP. M. Vanhoutte. 1989. Endothelium-derived relaxing and contracting factors.FASEB J. 3:2007–2018.

    PubMed  Google Scholar 

  2. Joyner, W. L., E. Svensjo, andK. E. Arfors. 1979. Simultaneous measurements of macromolecular leakage and arteriolar blood flow as altered by PGE1 and B2-receptor stimulant in the hamster cheek pouch.Microvasc. Res. 18:301–310.

    PubMed  Google Scholar 

  3. Yong, T., andW. G. Mayhan. 1992. Effect of prostaglandin E1 on leukotriene C4-induced increases in vascular permeability of hamster cheek pouch.Inflammation 16:159–167.

    PubMed  Google Scholar 

  4. Peck, M. J., P. J. Piper, andT. J. Williams. 1981. The effect of leukotrienes C4 and D4 on the microvasculature of guinea-pig skin.Prostaglandins 21:315–321.

    PubMed  Google Scholar 

  5. Mayhan, W. G. 1992. Role of nitric oxide in modulating permeability of the hamster cheek pouch in response to adenosine 5′-diphosphate and bradykinin.Inflammation 16:295–305.

    PubMed  Google Scholar 

  6. Moncada, S. 1990. The first Robert Furchgott lecture: From endothelium-dependent relaxation to thel-arginine: NO pathway.Blood Vessels 27:208–217.

    PubMed  Google Scholar 

  7. Masaki, T. 1993. Endothelins: Homeostatic and compensatory actions in the circulatory and endocrine systems.Endocrine Rev. 14:256–268.

    Google Scholar 

  8. Sakurai, T., andK. Goto. 1993. Endothelins. Vascular actions and clinical implications.Drugs 46:795–804.

    PubMed  Google Scholar 

  9. Chabrier, P. E., andP. Braquet. 1990. Endothelin.Horm. Res. 34:169–174.

    PubMed  Google Scholar 

  10. Randall, M. D. 1991. Vascular activities of the endothelins.Pharmacol. Ther. 50:73–93.

    PubMed  Google Scholar 

  11. Brain, S. D., G. Thomas, D. C. Crossman, R. Fuller, andM. K. Church. 1992. Endothelin-1 induces a histamine-dependent flare in vivo, but does not activate human skin mast cells in vitro.Br. J. Clin. Pharmacol. 33:117–120.

    PubMed  Google Scholar 

  12. Filep, J. G., M. G. Sirois, A. Rousseau, A. Fournier, andP. Sirois. 1991. Effects of endothelin-1 on vascular permeability in the conscious rat: Interactions with platelet-activating factor.Br. J. Pharmacol. 104:797–804.

    PubMed  Google Scholar 

  13. Sirois, M. G., J. G. Filep, A. Rousseau, A. Fournier, G. E. Plante, andP. Sirois. 1992. Endothelin-1 enhances vascular permeability in conscious rats: Role of thromboxane A2.Eur. J. Pharmacol. 214:119–125.

    PubMed  Google Scholar 

  14. Lehoux, S., G. E. Plante, M. G. Sirois, P. Sirois, andP. D'Orléans-Juste. 1992. Phosphoramidon blocks big-endothelin-1 but not endothelin-1 enhancement of vascular permeability in the rat.Br. J. Pharmacol. 107:996–1000.

    PubMed  Google Scholar 

  15. Filep, J. G., G. E. Foldes-Filep, A. Rousseau, P. Sirois, andA. Fournier. 1993. Vascular responses to endothelin-1 following inhibition of nitric oxide synthesis in the conscious rat.Br. J. Pharmacol. 110:1213–1221.

    PubMed  Google Scholar 

  16. Brain, S. D., D. C. Crossman, T. L. Buckley, andT. J. Williams. 1989. Endothelin-1: Demonstration of potent effects on the microcirculation of humans and other species.J. Cardiovasc. Pharmacol. 13:S147-S149.

    PubMed  Google Scholar 

  17. Chandler, C. L., A. R. Moore, F. M. Desa, D. W. Howat, andD. A. Willoughby. 1989. Anti-inflammatory effects of endothelin-1.J. Cardiovasc. Pharmacol. 13:S218-S219.

    PubMed  Google Scholar 

  18. Chander, C. L., A. R. Moore, F. M. Desa, D. Howat, andD. A. Willoughby. 1988. The local modulation of vascular permeability by endothelial cell derived products.J. Pharm. Pharmacol. 40:745–746.

    PubMed  Google Scholar 

  19. Haynes, W. G., andD. J. Webb. 1993. The endothelin family of peptides: Local hormones with diverse roles in health and disease.Clin. Sci. 84:485–500.

    PubMed  Google Scholar 

  20. Rubanyi, G. M., andL. H. P. Botelho. 1991. Endothelins.FASEB J. 5:2713–2720.

    PubMed  Google Scholar 

  21. Filep, J. G., M. G. Sirois, É. Földes-Filep, A. Rousseau, G. E. Plante, A. Fournier, M. Yano, andP. Sirois. 1993. Enhancement by endothelin-1 of microvascular permeability via the activation of ETA receptors.Br. J. Pharmacol. 109:880–886.

    PubMed  Google Scholar 

  22. Filep, J. G., É., Földes-Filep, A. Rousseau, A. Fournier, P. Sirois, andM. Yano. 1992. Endothelian-1 enhances vascular permeability in the rat heart through the ETA receptor.Eur. J. Pharmacol. 219:343–344.

    PubMed  Google Scholar 

  23. Mayhan, W. G., andW. L. Joyner. 1984. The effect of altering the external calcium concentration and a calcium channel blocker, verapamil, on microvascular leaky sites and dextran clearance in the hamster cheek pouch.Microvasc. Res. 28:159–179.

    PubMed  Google Scholar 

  24. Svensjo, E., andG. J. Grega. 1986. Evidence for endothelial cell mediated regulation of macromolecular permeability by postcapillary venules.Fed. Proc. 45:89–95.

    PubMed  Google Scholar 

  25. Olesen, S. P. 1987. Regulation of ion permeability in frog brain venules, significance of calcium, cyclic nucleotides and protein kinase C.J. Physiol. 387:59–68.

    PubMed  Google Scholar 

  26. Paul, J., A. Y. Bekker, andW. N. Duran. 1990. Calcium entry blockage prevents leakage of macromolecules induced by ischemia-reperfusion in skeletal muscle.Circ. Res. 66:1636–1642.

    PubMed  Google Scholar 

  27. Curry, F. E. 1992. Modulation of venular microvessel permeability of calcium influx into endothelial cells.FASEB J. 6:2456–2466.

    PubMed  Google Scholar 

  28. Joshua, I. G. 1990. Endothelin-induced vasoconstriction of small resistance vessels in the microcirculation of the rat cremaster muscle.Microvasc. Res. 40:191–198.

    PubMed  Google Scholar 

  29. Yanagisawa, M., H. Kurihara, S. Kimura, Y. Tomobe, M. Kobayashi, Y. Mitsui, Y. Yazaki, K. Goto, andT. Masaki. 1988. A novel potent vasoconstrictor peptide produced by vascular endothelial cells.Nature 332:411–415.

    PubMed  Google Scholar 

  30. Mayhan, W. G., G. Sahagun, R. Spector, andD. D. Heistad. 1986. Effects of leukotriene C4on the cerebral microvasculature.Am. J. Physiol. 251:H471-H474.

    PubMed  Google Scholar 

  31. Murray, M. A., D. D. Heistad, andW. G. Mayhan. 1991. Role of protein kinase C in bradykinin-induced increases in microvascular permeability.Circ. Res. 68:1340–1348.

    PubMed  Google Scholar 

  32. Mayhan, W. G. 1993. Role of nitric oxide in leukotriene C4-induced increases in microvascular transport.Am. J. Physiol. 265:H409-H414.

    PubMed  Google Scholar 

  33. Doherty, A. M., W. L. Cody, P. L. Depue, J. X. He, L. A. Waite, D. M. Leonard, N. L. Leitz, D. T. Dudley, S. T. Rapundalo, G. P. Hingoranis, S. J., Haleen, D. M. Ladouceur, K. E. Hill, M. A. Flynn, andE. E. Reynolds. 1993. Structure-activity relationships of C-terminal endothelin hexapeptide antagonists.J. Med. Chem. 36:2585–2594.

    PubMed  Google Scholar 

  34. Ihara, M., K. Noguchi, T. Saeki, T. Fukuroda, S. Tsuchida, S. Kimura, T. Fukami, K. Ishikawa, M. Nishikibe, andM. Yano. 1991. Biological profiles of highly potent novel endothelin antagonists selective for the ETA receptor.Life Sci. 50:247–255.

    Google Scholar 

  35. Yong, T., X. P. Gao, S. Koizumi, J. M. Conlon, S. I. Rennard, W. G. Mayhan, andI. Rubinstein. 1992. Role of peptidases in bradykinin-induced increase in vascular permeability in vivo.Circ. Res. 70:952–959.

    PubMed  Google Scholar 

  36. Svensjo, E., K. E. Andersson, E. Bouskela, F. Z. G. A. Cyrino, andS. Lindgren. 1993. Effects of two vasodilatory phosphodiesterase inhibitors on bradykinin-induced permeability in the hamster cheek pouch.Agents Actions 39:35–41.

    PubMed  Google Scholar 

  37. Svensjo, E., andW. L. Joyner. 1984. The effects of intermittent and continuous stimulation of microvessels in the cheek pouch of hamsters with histamine and bradykinin on the development of venular leaky sites.Microcirc. Endothel. Lymph. 1:381–396.

    Google Scholar 

  38. Svensjo, E. 1978. Bradykinin and prostaglandin E1, E2 and F2 alpha induced macromolecular leakage in the hamster cheek pouch.Prostaglandins Med. 1:397–410.

    PubMed  Google Scholar 

  39. Svensjo, E. 1978. Characterization of leakage of macromolecules in postcapillary venules.Acta Univ. Upsaliensis 34:1–42.

    Google Scholar 

  40. Svensjo, E., K. E. Arfors, R. M. Raymond, andG. J. Grega. 1979. Morphological and physiological correlation of bradykinin-induced macromolecular efflux.Am. J. Physiol. 236:H600-H606.

    PubMed  Google Scholar 

  41. Boric, M. P., J. S. Roblero, andW. N. Duran. 1987. Quantitation of bradykinin-induced microvascular leakage of FITC-dextran in rat cremaster muscle.Microvasc. Res. 33:397–412.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Physiology and Biophysics and Internal Medicine, University of Nebraska Medical Center, Omaha, 68198-4575, Nebraska

    William G. Mayhan & Israel Rubinstein

Authors
  1. William G. Mayhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Israel Rubinstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mayhan, W.G., Rubinstein, I. Effects of endothelin receptor antagonists on bradykinin-induced increases in macromolecular efflux. Inflammation 18, 633–644 (1994). https://doi.org/10.1007/BF01535261

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01535261

Keywords

Search

Navigation