Functional depression of isolated perfused rat heart mediated by activated leukocytes: protective effect of...

Langendorff rat heart preparations were perfused with suspensions of human leukocytes containing approximately 65% polymorphonuclear cells (PMN). The cells were either unstimulated or activated with 1.6 x 10(-8) phorbol 12-myristate 13-acetate (PMA). Left ventricular developed pressure (LVDP), coronary flow (CF), and heart rate (HR) were recorded during PMN infusion (10 min) and for the recovery period (30 min). PMN were also pretreated with cloricromene (CLO 10-50 microM), a drug that inhibits platelet aggregation and PMN adhesion to endothelial cells (EC). Infusion of unstimulated cells did not affect cardiac function. Infusion of activated cells caused CF reduction (-44 +/- 4% at end of infusion; -24 +/- 4% at end of recovery, expressed as percentage of variation vs. basal value), LVDP decrease (-44 +/- 5% at end of infusion, -26 +/- 6% at end of recovery) endothelial damage, and leukocyte accumulation in heart as compared with hearts infused with unstimulated PMN and sham hearts. PMN accumulation was quantified as myeloperoxidase (MPO) activity (260 +/- 35, 39 +/- 6, 19 +/- 1 U/g, respectively). Superoxide dismutase (SOD 600 U/ml), catalase (2,200 U/ml), thiourea (10 mM) added to PMN suspension blunted CF decrease but not LVDP reduction and MPO increase. CLO (25-50 microM) pretreatment inhibited PMN accumulation, LVDP, and CF reduction by approximately 50%. These data suggest a role of leukocyte activation in the genesis of heart damage and raise the possibility of a pharmacologic intervention with drugs such as CLO that can interfere with this process.