Tacrolimus limits polymorphonuclear leucocyte accumulation and protects against myocardial ischaemia-reperfusion injury

Intercellular adhesion molecule-1 (ICAM-1) plays an important role in the pathogenesis of either human and experimental myocardial ischaemia. Tacrolimus, formerly known as FK506, has been previously shown to display cardioprotective effects on experimental ischaemia/reperfusion-induced myocardial damage. This study investigated whether cardioprotection induced by tacrolimus in myocardial ischaemia-reperfusion (MI/R) injury might be due to inhibition of the nuclear factor kappa B (NF-κB) that in turn causes reduced cardiac ICAM-1 expression and blunted polymorphonuclear leukocyte accumulation. 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, serum creatine kinase (CK) activity, cardiac mRNA for ICAM-1 reverse-transcriptase polymerase chain reaction, the inhibitory protein of NF-κB IκBα (Western blot analysis) in the myocardium-at-risk, and left ventricle dP/dt(max) were evaluated. Myocardial ischaemia plus reperfusion in untreated rats produced marked myocardial necrosis, increased serum CK activity and myeloperoxidase activity (MPO, a marker of leukocyte accumulation) both in the area at risk and in the necrotic area, and reduced the left ventricle dP/dt(max). Furthermore, inhibitory protein IκBα levels decreased, and cardiac mRNA for ICAM-1 increased, after 0.5 and 5 h of reperfusion, respectively. Administration of tacrolimus (25. 50 and 100 μg/kg as an i.v, infusion 5 min after reperfusion) lowered myocardial necrosis and myeloperoxidase activity in the area at risk and in necrotic area, decreased serum CK activity, increased left ventricle dP/dt(max), reduced the loss the of inhibitory protein IκBα and blunted the message for ICAM-1. The present data suggest that tacrolimus blocks the early activation of the transcription factor NF-κB, suppresses ICAM-1 gene activation, reduces leukocyte accumulation and protects against myocardial ischaemia-reperfusion injury. (C) 2000 Academic Press.