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 tyrphostin AG 556, a tyrosine kinase inhibit or, on the phenomenon of leukocyte accumulation during ischaemia and reperf usion of the myocardium. Male anaesthetized rats were subjected to total oc clusion (45 min) of the left main coronary artery followed by 5 h reperfusi on (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 Facto r (TNF-alpha) and Interleukin 6 (IL-6), cardiac intercellular adhesion mole cule-1 (ICAM-1) and TNF-alpha expression and myocardial contractility (left ventricle dP/dt(max)) were evaluated. Myocardial ischaemia plus reperfusio n in untreated rats produced marked myocardial necrosis, increased serum CP K activity (196.5 +/- 19 U/100 mi, at the end of reperfusion) and myelopero xidase 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/tiss ue), reduced myocardial contractility (1,706 +/- 52 mmHg/s, at the end of r eperfusion) 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 t he end of reperfusion). Finally, myocardial ischaemia-reperfusion injury al so increased cardiac mRNA for TNF-alpha: and ICAM-1 in the myocardium-at ri sk. Tyrphostin AG 556 (0.5, I and 2 mg/kg subcutaneously 5 min after the on set of reperfusion) lowered myocardial necrosis and myeloperoxidase activit y 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), d ecreased serum CPK activity (96 +/- 9 U/100 mi, at the end of reperfusion), lowered serum TNF-alpha and IL-6, increased myocrtrdial contractility (2,0 96 +/- 88 mmHg s, at the end of reperfusion) and reduced cardiac mRNA level s for TNF-alpha and ICAM-1. The present data suggest that tyrosine kinase i nhibitors protect against myocardial ischaemia-reperfusion injury by reduci ng leukocyte accumulation to the ischaemic myocardium. (C) 2000 Elsevier Sc ience Inc. All rights reserved.