Inhibition of elastase improves myocardial function after repetitive ischaemia and myocardial infarction in the rat heart.
We investigated the potential of inhibition of elastase, a granulocyte-derived proteolytic enzyme, in ameliorating the effects of myocardial stunning caused by repetitive ischaemia (RI) and myocardial infarction (MI) for the first time in an in situ, perfused, rat heart model. The effects of the elastase-inhibitors Elafin (EL, 10 mg/kg/h) and ICI 200,880 (ICI,5 mg/kg/h) on myocardial blood flow (MBF, H2 clearance), regional myocardial function (FT, pulsed doppler) and neutrophil extravasation (myocardial myeloperoxidase activity, MPO) were investigated in RI (5x10 min ligature of the anterior descending ramus (LAD), 5x20 min reperfusion) and MI (50 min LAD ligature, 60 min reperfusion). Under control conditions, MBF and FT were significantly reduced and MPO was significantly increased after RI (n=8) and MI (n=8) in the ischaemic area compared with baseline. Pretreatment with EL (n=7) or ICI (n=7) did not improve MBF significantly and did not influence the successive attenuation of peak values of reactive hyperaemia. However, both EL and ICI significantly improved FT and significantly reduced MPO after RI and MI compared with control conditions. Additionally, both the area at risk and MI size were reduced significantly by both inhibitors. These results demonstrate that elastase inhibitors significantly improve the reduction of FT both in myocardial stunning and in myocardial infarction in the rat without significant improvement of MBF. It is concluded that elastase inhibitors exert a cardioprotective effect against reperfusion injury, probably by inhibition of leukocyte extravasation as indicated by the decrease in MPO activity.
Tiefenbacher
C P
CP
Department of Cardiology, University of Heidelberg, Bergheimerstrasse 58, D-69115 Heidelberg, Germany.
Ebert
M
M
Niroomand
F
F
Batkai
S
S
Tillmanns
H
H
Zimmermann
R
R
Kübler
W
W
D000818:Animals; D003326:Coronary Circulation; D005260:Female; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology*; D009504:Neutrophils / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology
D009842:Oligopeptides; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D015842:Serine Proteinase Inhibitors; C069695:ICI 200880; D009195:Peroxidase; D019272:Leukocyte Elastase