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 I κB α (Western blot analysis) in the myocardium-at-risk, and left ventricle d P/d tmaxwere 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/d tmax. Furthermore, inhibitory protein I κB α levels decreased, and cardiac mRNA for ICAM-1 increased, after 0.5 and 5 h of reperfusion, respectively. Administration of tacrolimus (25, 50 and 100μg/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/d tmax, reduced the loss the of inhibitory protein I κB α 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.