Background: Elastase release has been incriminated in the genesis of reperfusion-induced myocardial dysfunction and injury, and elastase inhibitors have been reported to reduce myocardial dysfunction in dogs subjected to coronary artery occlusion and reperfusion.
Methods and Results: To examine if efastase inhibition will modify myocardial dysfunction and injury induced by ischemia and reperfusion in isolated hearts, hearts from male Sprague Dawley rats were subjected to 30 minutes of total ischemia followed by 30 minutes of reper fusion. Ischemia-reperfusion resulted in myocardial dysfunction (increase in coronary perfu sion pressure and decrease in myocardial contraction), injury (measured as creatine kinase release), and lipid peroxidation (myocardial malondialdehyde). Perfusion of hearts with an elastase inhibitor, ICI200,880, protected against myocardial dysfunction, injury and lipid per oxidation following ischcmia-reperfusion. As expected, perfusion with superoxide dismutase protected the hearts against hemodynamic deterioration following ischemia-reperfusion. In in vitro studies, there was no direct effect of ICI200,880 on superoxide anion generation.
Conclusions: ICI200,880 seems to exert cardioprotective effects against ischemia-reperfu sion-induced injury and myocurdial dysfunction in isolated buffer-perfused hearts, most likely by an elastase-like protease inhibitory activity.
Mullane KM, Read N., Salmon JA, Moncada S.Role of leukocyte in acute myocardial infarction in anesthetized dogs: Relationship to myocardial salvage by anti-inflammatory drugs. J Pharmacol Exp Ther228:510, 1984
2.
Engler RL, Dahlgren MD, Morres D., Peterson MA, Schmid-Schoenbein G.Accumulation of polymorphonuclear leukocytes during 3 hour experimental ischemia . Am J Physiol251:H93, 1986
3.
Mehta JL, Nichols WW, Mehta P.Neutrophils as potential participants in acute myocardial ischemia. J Am Coll Cardiol11:1309, 1988
4.
Simpson PJ, Mitsos SE, Ventura A.Prostacyclin protects ischemic reperfused myocardium in the dog by inhibition of neutrophil activation. Am Heart J113:129, 1987
5.
Engler RL, Schmid-Schoenbein GW, Pavela R.Leukocyte capillary plugging in myocardial ischemia and reperfusion in the dog. Am J Pathol111:98, 1983
6.
Fanton JL, Ward PARole of oxygen derived free radicals and metabolites in leukocyte dependent inflammatory reaction. Am J Pathol107:394, 1982
7.
Jolly SR, Kane WF, Bailie MB, Abrams GD, Lucchesi BRCanine myocardial reperfusion injury: Its reduction by combined administration of superoxide dismutase and catalase. Circ Res54:277, 1984
8.
Dinerman JL, Mehta JL, Saldeen Tgp, Emerson S., Wallin R., Davda R., Davidson A.Increased neutrophil elastase release in unstable angina pectoris and acute myocardial infarction. J Am Coll Cardiol15:1559, 1990
Shimai S., Takano T., Seino Y., Tanaka K., Hayakawa H.Role of PMN elastase on ischemic myocardial injury in evolving myocardial infarction: Correlation with clinical parameters and intervention by protease inhibitor ulinastin. Jpn Circ J53:1144, 1989
11.
Zimmerman BJ , Granger DNReperfusion-induced leukocyte infiltration: Role of elastase. Am J Physiol259:H390, 1990
12.
Nicolini FA , Nichols WW, Saldeen Tgp, Mehta JLGeneration of superoxide radicals and release of elastase by neutrophils during thrombolysis [Abstract]. J Am Coll Cardiol15:32A, 1990
13.
Dinerman JL , Mehta JL, Saldeen Tgp, Emerson S., Wallin R., Davda R., Davidson A.: Increased neutrophil elastase release in unstable angina pectoris and acute myocardial infarction. J Am Coll Cardiol15:1559, 1990
14.
Jonas E., Dwenger A., Lueken B., Boehme U.Simultaneous measurement of endothelial cell damage, elastase release and chemiluminescence response during interaction between polymorphonuclear leukocytes and endothelial cells. J Biolumin Chemilumin6:19, 1991
15.
Inauen W., Granger DN, Meininger CJ, Schelling ME, Granger HI, Kvietys PRAnoxia-reoxygenation induced-, neutrophil-mediated endothelial cell injury: Role of elastase. Am J Physiol259:H925, 1990
16.
Nicolini FA , Mehta JL, Nichols WW, Donnelly WH, Luostarinen R., Saldeen Tgp.Leukocyte elastase inhibition and t-PA-induced coronary artery thrombolysis in dogs: Beneficial effects on myocardial histology . Am Heart J122:1245, 1991
17.
Baird BR, Cheronis JL, Sankhaus RA, Berger EM, White CW, Repine JEO2 metabolites and neutrophil elastase synergistically cause edematous injury in isolated rat lungs. J Appl Physiol561:2224, 1982
18.
Killackey JJ , Killackey BANeutrophil-mediated increased permeability of microcarrier-cultured endothelial monolayers: A model for the in vitro study of neutrophil-dependent ' mediators of vasopermeability. Can J Physiol Pharmacol68:836, 1990
19.
Linas SL, Whittenburg D., Parsons PE, Repine JEMild renal ischemia activates primed neutrophils to cause acute renal failure . Kidney Int42:610, 1992
20.
Mehta JL, Nichols WW, Nicolini FA, Hendricks J., Donnelly WH, Saldeen Tgp.Neutrophil elastase inhibitor ICI200,880 protects against attenuation of coronary flow reserve and myocardial dysfunction following temporary coronary artery occlusion in dogs. Cardiovasc Res28:947, 1994
21.
Thompson JA , Hess MLThe oxygen-free radical system: A fundamental mechanism in the production of myocardial necrosis. Prog Cardiovasc Dis28:449, 1986
22.
Yang BC, Nichols WW, Mehta JLCardiac effects of acetylcholine in isolated rat hearts: Role of endothelium-derived relaxing factor and prostaglandins. Am J Physiol264:H1388, 1993
23.
Yang BC, Virmani R., Nichols WW, Mehta JLPlatelets protect against myocardial dysfunction and injury induced by ischemia and reperfusion in isolated rat hearts. Circ Res72:1181, 1993
24.
Marklund S. , Marklund G.Involvement of superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase . Eur J Biochem74:469, 1974
25.
Lowry OH, Rosebrough NT, Lewis FAProtein measurement with the follin phenol reagent. J Biol Chem193:265, 1951
26.
Ohkawa H., Ohishi N., Yagi K.Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction . Anal Biochem95:351, 1979
27.
Todorovich-Hunter L., Dodo H., Ye C., McCready L., Kelley FW, Rabinovitch M.Increased pulmonary artery elastolytic activity in adult rats with monocrotaline-induced progressive hypertensive pulmonary vascular disease compared with infant rats with nonprogressive disease. Am Rev Resp Dis146:213, 1992
28.
Mehta JL, Lawson DL, Mehta P.Modulation of human neutrophil superoxide production by selective thromboxane synthetase inhibitor U63,577A. Life Sci43:923, 1988
Conner JG, Eckersall PD, Douglas TAInhibition of elastase by canine serum: Demonstration of an acute phase response . Res Vet Sci44:391, 1988
31.
Henson PM, Henson JE, Fittschen C., Barton DL, Riches Dwh.Degranulation and secretion by phagocytic cells. In JI Gallin, IM Goldstein, R Snyderman, inflammation: Basic Principles and Clinical Correlates , Raven Press, New York, pp. 511-539, 1992
32.
Yee TT, Suematsu M., Ohashi KL, DeLano FA, Kawabata K., Schmid-Schonbein GWRole of elastase in neutrophil adhesion and migration in vivo. Fed Am Soc Exp Biol J7:A907, 1993
33.
Phan SH, Gannon DE, Ward PA, Karmiol S.Mechanism of neutrophil-induced xanthine dehydrogenase to xanthine oxidase conversion in endothelial cells: Evidence of a role for elastase. Am J Resp Cell Mol Biol6:270, 1992
34.
Koster JF, Biemond P., Stam H.Lipid peroxidation and myocardial ischemic damage: Cause or consequence?Basic Res Cardiol82(suppl 1):253, 1987
35.
Arak H., Lefer AMRole of prostacyclin in the preservation of ischemic myocardial tissue in the perfused cat heart. Circ Res47:757, 1980
36.
Hayden RE, Paniello RC, Yeung CS, Bello SL, Dawson SMThe effect of glutathione and vitamins A, C and E on acute skin flap survival . Laryngoscope97:1176, 1987
37.
Hohlfeld T. , Strobach H., Schror K.Stimulation of prostacyclin synthesis by defibrotide: Improved contractile recovery from myocardial "stunning". J Cardiovasc Pharmacol17:108, 1991
38.
Ohnishi ST, Katsuoka M., Hidaka S.A prostaglandin oligomeric derivative inhibits activities of phospholipase and protease: A possible mechanism of membrane protection during ischemia . Cell Biochem Funct7:51, 1989
39.
Hornebeck W., Brechemier D., Soleihac JM, Bourdillon MC, Robert L.Extracellular matrix: Structure and function. In Reddi AH (ed). UCLA Symposia on Molecular and Cellular Biology New Series. Vol 25. Alan R. Liss, New York, pp. 269-282, 1984
