. Staphylococcal ␣-toxin provokes neutrophil-dependent cardiac dysfunction: role of ICAM-1 and cysleukotrienes. Am J Physiol Heart Circ Physiol 282: H1157-H1165, 2002; 10.1152/ajpheart.00165.2001.-The role of polymorphonuclear neutrophils (PMN) in septic myocardial dysfunction is presently unknown. Staphylococcus aureus infections are frequently associated with septic sequelae. Therefore, we perfused isolated rat hearts with low doses of ␣-toxin, the major staphylococcal exotoxin, followed by application of human PMN, N-formyl-methionyl-leucylphenylalanine, and arachidonic acid. In contrast to shamperfused hearts (no ␣-toxin), a rise in coronary perfusion pressure (CPP) and a reduction of contractile function were noted, and cardiac expression of intercellular adhesion molecule (ICAM)-1 was detected by immunohistochemical methods and real-time PCR. Histological analysis and myeloperoxidase activity indicated cardiac PMN accumulation in ␣-toxin-challenged hearts. Major quantities of cysteinyl (cys)-leukotrienes (LT), LTB4, and 5-hydroxyeicosatetraenoic acid (5-HETE) were found in the perfusate of ␣-toxin-exposed hearts. With an anti-ICAM-1 antibody, neutrophil accumulation, leukotriene (LT) synthesis, coronary vasoconstriction, and the accompanying cardiodepression were suppressed. Similarly, the lipoxygenase inhibitor MK-886 blocked LT synthesis and maintained cardiac function. We conclude that low-dose ␣-toxin provokes coronary endothelial ICAM-1 expression and neutrophil accumulation, with subsequent synthesis of cys-LTs, LTB4, and 5-HETE under conditions of appropriate stimulation. This response is linked with coronary vasoconstriction and contractile dysfunction, with cys-LT synthesis and maldistribution of perfusion offered as likely underlying mechanisms. bacterial exotoxins; septic heart dysfunction; neutrophil mediators PROGRESSIVE MYOCARDIAL dysfunction, characterized by dilatation and reduced ejection fractions of both ventricles (33, 34), contributes to the cardiocirculatory abnormalities of septic shock. Despite the clinical importance of this disease (35), the pathogenetic mechanisms leading to the loss of myocardial function in sepsis are still not fully elucidated. Cardiodepressant effects of cytokines, predominantly tumor necrosis factor-␣ and interleukin-1␤, have been implicated in the development of cardiac depression in sepsis (26,27). In addition, experimental data suggest that-despite preserved coronary blood flow in sepsis (10)-impairment of coronary vasoregulation and myocardial regional perfusion may also depress cardiac performance (7,13,22,40). Moreover, there is recent experimental evidence that recruitment and activation of polymorphonuclear neutrophils (PMN) may also contribute to the development of septic myocardial failure. In endotoxemic animals PMN have been shown to accumulate in the myocardium (3, 14), and very recently it was demonstrated that leukocytes originating from endotoxemic rabbits are retained in the coronary circulation of isolated hearts and cause contractile dysfu...