Basic Research in Cardiology

, Volume 91, Issue 4, pp 289–295 | Cite as

Inhibition of granulocyte-derived proteases reduces the increase in plasma endothelin associated with myocardial ischemia in the pig

  • T. Tønnessen
  • A. Ilebekk
  • P. A. Naess
  • G. Christensen
Original Contribution

Abstract

Plasma endothelin (ET) is increased in association with myocardial infarction. The aim of the present study was to get insight into the mechanisms behind this ischemiainduced increase in plasma ET. Since granulocytes increase ET production in vitro, we examined to what extent inhibition of granulocyte-derived proteases could reduce the increase in plasma ET observed in association with myocardial ischemia. We infused Eglin C, a selective inhibitor of the granulocyte-derived proteases elastase, cathepsin G, and chymotrypsin, in pigs subjected to 90 min left anterior descending coronary artery occlusion followed by 210 min reperfusion (n=7). Arterial plasma ET increased in an untreated control group (n=7) from 5.0±0.6 (mean ±SEM) fmol· ml−1 before myocardial ischemia to 6.1±0.6 fmol·ml−1 at 90 min ischemia and reached a maximum of 6.8±0.9 fmol·ml−1 at 90 min reperfusion. The increase in plasma ET associated with myocardial ischemia was almost completely abolished in the Eglin C treated group (p=0.005). Plasma ET in the Eglin C treated animals was 4.7±0.4,4.7±0.4, and 4.6±0.4 fmol· ml−1 before myocardial ischemia, at 90 min ischemia, and at 90 min reperfusion, respectively. Our study suggests a role for granulocytederived proteases in the increase in plasma ET associated with myocardial ischemia. We have shown that the increase in plasma ET associated with myocardial ischemia was reduced by inhibition of granulocytederived proteases using the selective protease inhibitor Eglin C.

Key words

Endothelin Eglin C proteases ischemia granulocytes 

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References

  1. 1.
    Froeschle MC, Goetz WA (eds) (1985) Elastase — a new marker for inflammatory diseases. GIT Verlag Darmstadt, pp 1–44Google Scholar
  2. 2.
    Grover GJ, Dzwonczyk S, Parham CS (1993) The endothelin-1 receptor antagonist BQ-123 reduces infarct size in a canine model of coronary occlusion and reperfusion. Cardiovasc Res 27: 1613–1618Google Scholar
  3. 3.
    Hirata Y, Takagi Y, Fukuda Y, Marumo F (1989) Endothelin is a potent mitogen for rat vascular smooth muscle cells. Atherosclerosis 78:225–228Google Scholar
  4. 4.
    Ishikawa T, Yanagisawa M, Kimura S, Goto K, Masaki T (1988) Positive chronotropic effects of endothelin, a novel endothelium-derived vasoconstrictor peptide. Pflugers Arch 413:108–110Google Scholar
  5. 5.
    Ito H, Hirata Y, Hiroe M, Tsujino M, Adachi S, Takamoto T, Nitta M, Taniguchi K, Marumo F (1991) Endothelin-1 induces hypertrophy with enhanced expression of muscle-specific genes in cultured neonatal rat cardiomyocytes. Circ Res 69:209–215Google Scholar
  6. 6.
    Kaw S, Hecker M, Vane JR (1992) The two-step conversion of big endothelin 1 to endothelin 1 and degradation of endothelin 1 by subcellular fractions from human polymorphonuclear leukocytes. Proc Natl Acad Sci USA 89:6886–6890Google Scholar
  7. 7.
    Kelly RA, Eid H, Kramer BK, O'Neill M, Liang BT, Reers M, Smith TW (1990) Endothelin enhances the contractile responsiveness of adult rat ventricular myocytes to calcium by a pertussis toxinsensitive pathway. J Clin Invest 86: 1164–1171Google Scholar
  8. 8.
    Kusumoto K, Awane Y, Fujiwara S, Watanabe T (1993) Role of endogenous endothelin in extension of rabbit myocardial infarction. J Cardiovasc Pharmacol 22 Suppl 8:S339-S342Google Scholar
  9. 9.
    Lee JY, Warner RB, Adler AL, Opgenorth TJ (1994) Endothelin ETA receptor antagonist reduces myocardial infarction induced by coronary artery occlusion and reperfusion in the rat. Pharmacology 49:319–324Google Scholar
  10. 10.
    Lerman A, Hildebrand FL Jr, Aarhus LL, Burnett JC Jr (1991) Endothelin has biological actions at pathophysiological concentrations. Circulation 83:1808–1814Google Scholar
  11. 11.
    Miyauchi T, Yanagisawa M, Tomizawa T, Sugishita Y, Suzuki N, Fujino M, Ajisaka R, Goto K, Masaki T (1989) Increased plasma concentrations of endothelin-1 and big endothelin-1 in acute myocardial infarction. Lancet 2: 53–54Google Scholar
  12. 12.
    Morita T, Kurihara H, Yoshizumi M, Maemura K, Sugiyama T, Nagai R, Yazaki Y (1993) Human polymorphonuclear leukocytes have dual effects on endothelin-1: the induction of endothelin-1 mRNA expression in vascular endothelial cells and modification of the endothelin-1 molecule. Heart Vessels 8:1–6Google Scholar
  13. 13.
    Offstad J, Tønnessen T, Kirkebøen KA, Ilebekk A, Downing SE (1995) Modulation of systolic and diastolic function by endothelin-1: Relation to coronary flow. Acta Physiol Scand 154:103–111Google Scholar
  14. 14.
    Patrignani P, Del Maschio A, Bazzoni G, Daffonchio L, Hernandez A, Modica R, Montesanti L, Volpi D, Patrono C, Dejana E (1991) Inactivation of endothelin by polymorphonuclear leukocytederived lytic enzymes. Blood 78:2715–2720Google Scholar
  15. 15.
    Salminen K, Tikkanen I, Saijonmaa O, Nieminen M, Fyhrquist F, Frick MH (1989) Modulation of coronary tone in acute myocardial infarction by endothelin. Lancet 2:747Google Scholar
  16. 16.
    Sawamura T, Kimura S, Shinmi O, Sugita Y, Kobayashi M, Mitsui Y, Yanagisawa M, Goto K, Masaki T (1990) Characterization of endothelin converting enzyme activities in soluble fraction of bovine cultured endothelial cells. Biochem Biophys Res Commun 169: 1138–1144Google Scholar
  17. 17.
    Schnebli HP, Seemüller U, Fritz H, Maschler R, Liersch M, Virca GD, Bodmer JL, Snider GL, Lucey EC, Stone PG (1985) Eglin C, a pharmacologically active elastase inhibitor. Eur J Respir Dis 66, Suppl 139:66–70Google Scholar
  18. 18.
    Seemüller U, Meier M, Ohlsson K, Müller HP, Fritz H (1977) Isolation and characterization of a low molecular weight inhibitor (of chymotrypsin and human granulocytic elastase and cathepsin G) from leeches. Hoppe Seyler's Z Physiol Chem 358:1105–1117Google Scholar
  19. 19.
    Sessa WC, Kaw S, Hecker M, Vane JR (1991) The biosynthesis of endothelin-1 by human polymorphonuclear leukocytes. Biochem Biophys Res Commun 174:613–618Google Scholar
  20. 20.
    Siebeck M, Hoffmann H, Jochum M, Fritz H (1989) Inhibition of proteinases with recombinant eglin c during experimental escherichia coli septicemia in the pig. Eur Surg Res 21:11–17Google Scholar
  21. 21.
    Stawski G, Bang Olsen U, Grande P (1991) Cytotoxic effect of endothelin-1 during ‘simulated’ ischemia in cultured rat myocytes. Eur J Pharmacol 201:123–124Google Scholar
  22. 22.
    Tsuji S, Sawamura A, Watanabe H, Takihara K, Park SE, Azuma J (1991) Plasma endothelin levels during myocardial ischemia and reperfusion. Life Sci 48:1745–1749Google Scholar
  23. 23.
    Tønnessen T, Giaid A, Saleh D, Naess PA, Yanagisawa M, Christensen G (1995) Increased in vivo expression and production of endothelin-1 by porcine cardiomyocytes subjected to ischemia. Circ Res 76:767–772Google Scholar
  24. 24.
    Tønnessen T, Naess PA, Kirkebøen KA, Offstad J, Ilebekk A, Christensen G (1993) Release of endothelin from the porcine heart after short term coronary artery occlusion. Cardiovasc Res 27: 1482–1485Google Scholar
  25. 25.
    Tønnessen T, Schlichting E, Lyberg T, Christensen G (1995) Inhibition of granulocyte-derived proteases abolishes endothelin-1 release and reduces mortality associated with intestinal ischemia and reperfusion in the pig. Endothelium 3:225–234Google Scholar
  26. 26.
    Uprichard ACG, Chi L, Lucchesi BR (1993) Functional consequence of big endothelin conversion: Demonstration with isolated neutrophils but not in a postinfarction model. Pharmacology 47: 277–285Google Scholar
  27. 27.
    Wang QD, Li XS, Lundberg JM, Pernow J (1995) Protective effects of nonpeptide endothelin receptor antagonist bosentan on myocardial ischaemic and reperfusion injury in the pig. Cardiovasc Res 29:805–812Google Scholar
  28. 28.
    Watanabe T, Suzuki N, Shimamoto N, Fujino M, Imada A (1993) Contribution of endogenous endothelin to the extension of myocardial infarct size in rats. Circ Res 69:370–377Google Scholar
  29. 29.
    Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332:411–415Google Scholar

Copyright information

© Steinkopff Verlag 1996

Authors and Affiliations

  • T. Tønnessen
    • 1
  • A. Ilebekk
    • 1
  • P. A. Naess
    • 1
  • G. Christensen
    • 1
  1. 1.Institute for Experimental Medical ResearchUllevål HospitalOsloNorway

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