The reduction of myocardial damage and leukocyte polymorphonuclear accumulation following coronary artery occlusion by the tyrosine kinase inhibitor tyrphostin AG 556.
We investigated the effects of tyrophostin AG 556, a tyrosine kinase inhibitor, on the phenomenon of leukocyte accumulation during ischaemia and reperfusion of the myocardium. Male anaesthetized rats were subjected to total occlusion (45 min) of the left main coronary artery followed by 5 h reperfusion (MI/R). Sham myocardial ischaemia-reperfusion rats (Sham MI/R) were used as controls. Myocardial necrosis, myocardial myeloperoxidase activity (MPO), serum creatinine phosphokinase activity (CPK) serum Tumor Necrosis Factor (TNF-alpha) and Interleukin 6 (IL-6), cardiac intercellular adhesion molecule-1 (ICAM-1) and TNF-alpha expression and myocardial contractility (left ventricle dP/dt(max)) were evaluated. Myocardial ischaemia plus reperfusion in untreated rats produced marked myocardial necrosis, increased serum CPK activity (196.5 +/- 19 U/100 ml, at the end of reperfusion) and myeloperoxidase activity (MPO, a marker of leukocyte accumulation) both in the area-at-risk (4.5 +/- 0.5 U/g/tissue) and in necrotic area (8.2 +/- 1.2 U/g/tissue), reduced myocardial contractility (1,706 +/- 52 mmHg/s, at the end of reperfusion) and induced a marked increase in the serum levels of TNF-alpha (1,950 +/- 97 pg/ml, at 1 h of reperfusion) and IL-6 (998 +/- 16 U/ml, at the end of reperfusion). Finally, myocardial ischaemia-reperfusion injury also increased cardiac mRNA for TNF-alpha and ICAM-1 in the myocardium-at risk. Tyrphostin AG 556 (0.5, 1 and 2 mg/kg subcutaneously 5 min after the onset of reperfusion) lowered myocardial necrosis and myeloperoxidase activity in the area-at-risk (1.5 +/- 0.2 U/g/tissue, following the highest dose) and in necrotic area (2.9 +/- 0.3 U/g/tissue following the highest dose), decreased serum CPK activity (96 +/- 9 U/100 ml, at the end of reperfusion), lowered serum TNF-alpha and IL-6, increased myocardial contractility (2,096 +/- 88 mmHg s, at the end of reperfusion) and reduced cardiac mRNA levels for TNF-alpha and ICAM-1. The present data suggest that tyrosine kinase inhibitors protect against myocardial ischaemia-reperfusion injury by reducing leukocyte accumulation to the ischaemic myocardium.
Altavilla
D
D
Institute of Pharmacology, School of Medicine, University of Messina, Italy. daltavilla@unime.it
Squadrito
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Campo
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GM
Saitta
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A
Squadrito
G
G
Quartarone
C
C
Deodato
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B
Arlotta
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M
Ferlito
M
M
Minutoli
L
L
Tringali
M
M
Urna
G
G
Sardella
A
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Caputi
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AP
D000818:Animals; D003327:Coronary Disease / Q000150:complications* / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000097:blood / Q000235:genetics; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood / Q000235:genetics; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D009336:Necrosis; D009504:Neutrophils / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics; D020032:Tyrphostins / Q000627:therapeutic use*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D004791:Enzyme Inhibitors; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D020032:Tyrphostins; D018799:Intercellular Adhesion Molecule-1; C098981:AG 556; D009195:Peroxidase; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D011505:Protein-Tyrosine Kinases; D003402:Creatine Kinase