Skip to main content
SpringerLink
Log in

B2 kinin receptor activation is the predominant mechanism by which trypsin mediates endothelium-dependent relaxation in bovine coronary arteries

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

The roles of kinin and protease-activated receptors (PAR) in endothelium-dependent relaxations to the serine protease, trypsin, were examined in rings of bovine left anterior descending coronary artery (LAD). Trypsin (0.01–30 U/ml) caused biphasic, endothelium-dependent relaxations—a high potency (0.01–0.3 U/ml), low efficacy relaxation [maximum relaxation (R max), 9.0 ± 5.1%] followed by a lower potency (1–30 U/ml) but high efficacy (R max, 90.4 ± 5.5%) relaxation, which was abolished by aprotinin. Captopril (10 μM) caused an ~10-fold leftward shift of the second phase response such that the first phase was masked. The second phase relaxation to trypsin was inhibited in a concentration-dependent, non-surmountable manner by the B2 antagonist, HOE-140. At 3 nM HOE-140, the second phase response to trypsin was abolished unmasking the first phase. Kallikrein (0.0003–0.3 U/ml) caused monophasic, endothelium-dependent relaxations (R max, 33.7 ± 14.6%), which were potentiated by captopril (R max, 94.2 ± 1.0%) and abolished by HOE-140. In the presence of captopril, the second phase relaxation to trypsin was only minimally inhibited by either NG-nitro-l-arginine (100 μM) or 67 mM [K+]o alone but markedly reduced when these two treatments were combined (R max, 26.1 ± 11.6% versus 98.6 ± 2.9% in controls). The PAR1-activating peptide, SFLLRN (0.1–30 μM), but not the PAR2-activating peptide, SLIGRL, caused concentration-dependent relaxations (pEC50, 5.9 ± 0.0%; R max, 43.3 ± 8.3%). In conclusion, trypsin causes endothelium-dependent relaxations in the bovine LAD predominantly via release of endogenous BK, which in turn activates endothelial B2 receptors. Only a minor role for PAR1-like receptors was evident in this tissue.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Auch-Schwelk W, Bossaller C, Claus M, Graf K, Grafe M, Fleck E (1992) Local potentiation of bradykinin-induced vasodilation by converting-enzyme inhibition in isolated coronary arteries. J Cardiovasc Pharmacol 20:S62–S67

    Article  PubMed  CAS  Google Scholar 

  • Blackhart BD, Emilsson K, Nguyen D, Teng W, Martelli AJ, Nystedt S, Sundelin J, Scarborough RM (1996) Ligand cross-reactivity within the protease-activated receptor family. J Biol Chem 271:16466–16471

    Article  PubMed  CAS  Google Scholar 

  • Cocks TM, Moffatt JD (2000) Protease-activated receptors: sentries for inflammation? Trends Pharmacol Sci 21:103–108

    Article  PubMed  CAS  Google Scholar 

  • Colman RW, Pixley RA, Najamunnisa S, Yan W, Wang J, Mazar A, McCrae KR (1997) Binding of high molecular weight kininogen to human endothelial cells is mediated via a site within domains 2 and 3 of the urokinase receptor. J Clin Invest 100:1481–1487

    Article  PubMed  CAS  Google Scholar 

  • De Mey JG, Vanhoutte PM (1981) Role of the intima in the relaxation of the canine femoral artery caused by thrombin. Arch Int Pharmacodyn Ther 250:314–315

    PubMed  Google Scholar 

  • De Mey JG, Claeys M, Vanhoutte PM (1982) Endothelium-dependent inhibitory effects of acetylcholine, adenosine triphosphate, thrombin and arachidonic acid in the canine femoral artery. J Pharmacol Exp Ther 222:166–173

    PubMed  Google Scholar 

  • Derkach DN, Ihara E, Hirano K, Nishimura J, Takahashi S, Kanaide H (2000) Thrombin causes endothelium-dependent biphasic regulation of vascular tone in the porcine renal interlobar artery. Br J Pharmacol 131:1635–1642

    Article  PubMed  CAS  Google Scholar 

  • Drummond GR, Cocks TM (1995) Endothelium-dependent relaxations mediated by inducible B1 and constitutive B2 kinin receptors in the bovine isolated coronary artery. Br J Pharmacol 116:2473–2481

    PubMed  CAS  Google Scholar 

  • Drummond GR, Cocks TM (1996) Evidence for mediation by endothelium-derived hyperpolarizing factor of relaxation to bradykinin in the bovine isolated coronary artery independently of voltage-operated Ca2+ channels. Br J Pharmacol 117:1035–1040

    PubMed  CAS  Google Scholar 

  • Drummond GR, Selemidis S, Cocks TM (2000) Apamin-sensitive, non-nitric oxide (NO) endothelium-dependent relaxations to bradykinin in the bovine isolated coronary artery: no role for cytochrome P450 and K+. Br J Pharmacol 129:811–819

    Article  PubMed  CAS  Google Scholar 

  • Fields T, Ghebrehiwet B, Kaplan AP (1983) Kinin formation in hereditary angioedema plasma: evidence against kinin derivation from C2 and in support of “spontaneous” formation of bradykinin. J Allergy Clin Immunol 72(1):54–60

    Article  PubMed  CAS  Google Scholar 

  • Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376

    Article  PubMed  CAS  Google Scholar 

  • Glusa E, Saft A, Prasa D, Sturzebecher J (1997) Trypsin- and SLIGRL-induced vascular relaxation and the inhibition by benzamidine derivatives. Thromb Haemost 78:1399–1403

    PubMed  CAS  Google Scholar 

  • Hamilton JR, Cocks TM (2000) Heterogeneous mechanisms of endothelium-dependent relaxation for thrombin and peptide activators of protease-activated receptor-1 in porcine isolated coronary artery. Br J Pharmacol 130:181–188

    Article  PubMed  CAS  Google Scholar 

  • Hamilton JR, Nguyen PB, Cocks TM (1998) Atypical protease-activated receptor mediates endothelium-dependent relaxation of human coronary arteries. Circ Res 82:1306–1311

    PubMed  CAS  Google Scholar 

  • Hamilton JR, Moffatt JD, Frauman AG, Cocks TM (2001) Protease-activated receptor (PAR) 1 but not PAR2 or PAR4 mediates endothelium-dependent relaxation to thrombin and trypsin in human pulmonary arteries. J Cardiovasc Pharmacol 38:108–119

    Article  PubMed  CAS  Google Scholar 

  • Hasan AA, Cines DB, Ngaiza JR, Jaffe EA, Schmaier AH (1995) High-molecular-weight kininogen is exclusively membrane bound on endothelial cells to influence activation of vascular endothelium. Blood 85:3134–3143

    PubMed  CAS  Google Scholar 

  • Hasan AA, Zisman T, Schmaier AH (1998) Identification of cytokeratin 1 as a binding protein and presentation receptor for kininogens on endothelial cells. Proc Natl Acad Sci U S A 95:3615–3620

    Article  PubMed  CAS  Google Scholar 

  • Hecquet C, Tan F, Marcic BM, Erdos EG (2000) Human bradykinin B(2) receptor is activated by kallikrein and other serine proteases. Mol Pharmacol 58:828–836

    PubMed  CAS  Google Scholar 

  • Herwald H, Dedio J, Kellner R, Loos M, Muller-Esterl W (1996) Isolation and characterization of the kininogen-binding protein p33 from endothelial cells. Identity with the gC1q receptor. J Biol Chem 271:13040–13047

    Article  PubMed  CAS  Google Scholar 

  • Hirano K, Kanaide H (2003) Role of protease-activated receptors in the vascular system. J Atheroscler Thromb 10:211–225

    PubMed  CAS  Google Scholar 

  • Hollenberg MD, Saifeddine M, Al-Ani B, Gui Y (1999) Proteinase-activated receptor 4 (PAR4): action of PAR4-activating peptides in vascular and gastric tissue and lack of cross-reactivity with PAR1 and PAR2. Can J Physiol Pharm 77:458–464

    Article  CAS  Google Scholar 

  • Hwa JJ, Ghibaudi L, Williams P, Chintala M, Zhang R, Chatterjee M, Sybertz E (1996) Evidence for the presence of a proteinase-activated receptor distinct from the thrombin receptor in vascular endothelial cells. Circ Res 78:581–588

    PubMed  CAS  Google Scholar 

  • Ku DD (1982) Coronary vascular reactivity after acute myocardial ischemia. Science 218:576–578

    Article  PubMed  CAS  Google Scholar 

  • Ku DD (1986) Mechanism of thrombin-induced endothelium-dependent coronary vasodilation in dogs: role of its proteolytic enzymatic activity. J Cardiovasc Pharmacol 8:29–36

    PubMed  CAS  Google Scholar 

  • Moffatt JD, Cocks TM (1998) Endothelium-dependent and -independent responses to protease-activated receptor-2 (PAR-2) activation in mouse isolated renal arteries. Br J Pharmacol 125:591–594

    Article  PubMed  CAS  Google Scholar 

  • Mombouli JV, Illiano S, Nagao T, Scott-Burden T, Vanhoutte PM (1992) Potentiation of endothelium-dependent relaxations to bradykinin by angiotensin I converting enzyme inhibitors in canine coronary artery involves both endothelium-derived relaxing and hyperpolarizing factors. Circ Res 71:137–144

    PubMed  CAS  Google Scholar 

  • Moroi M, Akatsuka N, Fukazawa M, Hara K, Ishikawa M, Aikawa J, Namiki A, Yamaguchi T (1994) Endothelium-dependent relaxation by angiotensin-converting enzyme inhibitors in canine femoral arteries. Am J Physiol 266:H583–H589

    PubMed  CAS  Google Scholar 

  • Nishikawa K, Shibayama Y, Kuna P, Calcaterra E, Kaplan AP, Reddigari SR (1992) Generation of vasoactive peptide bradykinin from human umbilical vein endothelium-bound high molecular weight kininogen by plasma kallikrein. Blood 80:1980–1988

    PubMed  CAS  Google Scholar 

  • Nystedt S, Emilsson K, Wahlestedt C, Sundelin J (1994) Molecular cloning of a potential proteinase activated receptor. Proc Natl Acad Sci U S A 91:9208–9212

    Article  PubMed  CAS  Google Scholar 

  • Ossovskaya VS, Bunnet NW (2004) Protease-activated receptors: contribution to physiology and disease. Physiol Rev 84:579–621

    Article  PubMed  CAS  Google Scholar 

  • Regoli D, Barabe J (1980) Pharmacology of bradykinin and related kinins. Pharmacol Rev 32:1–46

    PubMed  CAS  Google Scholar 

  • Rocha e Silva M, Beraldo WT, Rosenfield G (1949) Bradykinin, a hypotensive and smooth muscle stimulating factor released from plasma globulin by snake venoms and by trypsin. Am J Physiol 156:261–273

    PubMed  Google Scholar 

  • Schmaier AH, Kuo A, Lundberg D, Murray S, Cines DB (1988) The expression of high molecular weight kininogen on human umbilical vein endothelial cells. J Biol Chem 263:16327–16333

    PubMed  CAS  Google Scholar 

  • Steinberg SF (2005) The cardiovascular actions of protease-activated receptors. Mol Pharmacol 67:2–11

    Article  PubMed  CAS  Google Scholar 

  • van Iwaarden F, de Groot PG, Bouma BN (1988a) The binding of high molecular weight kininogen to cultured human endothelial cells. J Biol Chem 263:4698–4703

    PubMed  Google Scholar 

  • van Iwaarden F, de Groot PG, Sixma JJ, Berrettini M, Bouma BN (1988b) High-molecular weight kininogen is present in cultured human endothelial cells: localization, isolation, and characterization. Blood 71:1268–1276

    PubMed  Google Scholar 

  • Vu TK, Hung DT, Wheaton VI, Coughlin SR (1991) Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64:1057–1068

    Article  PubMed  CAS  Google Scholar 

  • Ward PE (1991) Metabolism of bradykinin and bradykinin analogs. In: Burch, RM (eds) Bradykinin antagonists: basic and clinical research. Dekker, New York, pp 147–170

    Google Scholar 

  • Zhang JJ, Chao L, Chao J (1999) Adenovirus-mediated kallikrein gene delivery reduces aortic thickening and stroke-induced death rate in Dahl salt-sensitive rats. Stroke 30:1925–1931; discussion 1931–1922

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Health and Medical Research Council of Australia (NHMRC) and National Heart Foundation of Australia. GRD is supported by a Monash Category I Fellowship, while fellowships from the NHMRC provide support for SS and TMC.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Monash University, Clayton, Victoria, Australia

    Grant R. Drummond & Stavros Selemidis

  2. Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia

    Thomas M. Cocks

Authors
  1. Grant R. Drummond
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stavros Selemidis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas M. Cocks
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Grant R. Drummond.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Drummond, G.R., Selemidis, S. & Cocks, T.M. B2 kinin receptor activation is the predominant mechanism by which trypsin mediates endothelium-dependent relaxation in bovine coronary arteries. Naunyn-Schmied Arch Pharmacol 378, 33–41 (2008). https://doi.org/10.1007/s00210-008-0291-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-008-0291-x

Keywords

Search

Navigation