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

Intercellular adhesion molecule-1 (ICAM-1) plays an important role in the p athogenesis of either human and experimental myocardial ischaemia, Tacrolim us, formerly known as FK506, has been previously shown to display cardiopro tective effects on experimental ischaemia/reperfusion-induced myocardial da mage. This study investigated whether cardioprotection induced by tacrolimu s in myocardial ischaemia-reperfusion (MI/R) injury might be due to inhibit ion of the nuclear factor kappa B (NF-kappa B) that in turn causes reduced cardiac ICAM-1 expression and blunted polymorphonuclear leukocyte accumulat ion. Anaesthetized rats were subjected to total occlusion (45 min) of the l eft main coronary artery followed by 5 h reperfusion (MI/R). Sham myocardia l ischaemia-reperfusion rats (Sham MI/R) were used as controls. Myocardial necrosis, myocardial myeloperoxidase activity, serum creatine kinase (CK) a ctivity, cardiac mRNA for ICAM-1 reverse-transcriptase polymerase chain rea ction, the inhibitory protein of NF-kappa B I kappa B alpha (Western blot a nalysis) in the myocardium-at-risk, and left ventricle dP/dt(max) were eval uated, Myocardial ischaemia plus reperfusion in untreated rats produced mar ked myocardial necrosis, increased serum CK activity and myeloperoxidase ac tivity (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). Furthe rmore, inhibitory protein I kappa B alpha levels decreased, and cardiac mRN A for ICAM-1 increased, after 0.5 and 5 h of reperfusion, respectively. Adm inistration of tacrolimus (25, 50 and 100 mu g/kg as an i.v. infusion 5 min after reperfusion) lowered myocardial necrosis and myeloperoxidase activit y in the area at risk and in necrotic area, decreased serum CK activity, in creased left ventricle dP/dt(max) reduced the loss the of inhibitory protei n I kappa B alpha and blunted the message for ICAM-1. The present data sugg est that tacrolimus blocks the early activation of the transcription factor NF-kappa B, suppresses ICAM-1 gene activation, reduces leukocyte accumulat ion and protects against myocardial ischaemia-reperfusion injury. (C) 2000 Academic Press.