Cyclosporin-A reduces leukocyte accumulation and protects against myocardial ischaemia reperfusion injury in rats

The present study was designed to evaluate the effect of cyclosporin A in a rat model of myocardial ischaemia reperfusion injury (MI/R). Anaesthetized rats were subjected to total occlusion (20 min) of the left main coronary artery followed by 5 h reperfusion (MI/R). Sham myocardial ischaemia-reperf usion rats (Sham MI/R) were used as controls. Myocardial necrosis, myocardi al myeloperoxidase activity (MPO), serum creatinine phosphokinase activity (CPK), serum tumor necrosis factor (TNF-alpha), cardiac mRNA for TNF-alpha, cardiac intercellular adhesion molecule-1 (ICAM-1) immunostaining and myoc ardial contractility (left ventricle dP/dt(max)) were evaluated. Myocardial ischaemia plus reperfusion in untreated rats produced marked myocardial ne crosis, increased serum CPK activity and myeloperoxidase activity (a marker of leukocyte accumulation) both in the area-at-risk and in the necrotic ar ea, reduced myocardial contractility and induced a marked increase in the s erum levels of the TNF-alpha. Furthermore increased cardiac mRNA for TNF-al pha was measurable within 10 to 20 min of left main coronary artery occlusi on in the area-at-risk and increased levels were generally sustained for 0. 5 h. Finally, myocardial ischaemia-reperfusion injury increased ICAM-1 stai ning in the myocardium. Administration of cyclosporin A (0.25, 0.5 and 1 mg /kg as an i.v. infusion 5 min after coronary artery occlusion) lowered myoc ardial necrosis and myeloperoxidase activity in the area-at-risk and in the necrotic area, decreased serum CPK activity, increased myocardial contract ility, reduced serum levels of TNF-alpha and the cardiac cytokine mRNA leve ls, and blunted ICAM-1 immunostaining in the injured myocardium. The data s uggest that cyclosporin A suppresses leukocyte accumulation and protects ag ainst myocardial ischaemia-reperfusion injury. (C) 1999 Elsevier Science B. V. All rights reserved.