RATIONALE: Ischaemic heart disease is the leading cause of mortality in the western world. In ischaemic heart disease, the myocardium may be at risk of injury from the products of cell necrosis, such as histones. Histones, which are released into extracellular circulation from the nuclei of necrotic cells, are cytotoxic (Xu et al., 2009). Histone-induced toxicity is mediated through direct cellular membrane interaction and resultant cation influx. The aim of this study was to investigate the effects of histones on Ca2+ regulation, contractility and viability in rat ventricular myocytes. METHODS: Ventricular myocytes were isolated from healthy male adults Wistar rats (200-250 g) that had been killed humanely using an ethically approved Schedule 1 procedure. First, electrically stimulated myocytes (1Hz), loaded with fura-2 AM, were superfused at 30°C with a normal Tyrode solution in the absence and presence of H3 (3.0 µg/ml) or Hmix (H1-H2A-H2B-H3-H4-H5; 3.0 µg/ml) for a maximum of 10 min. Second, this was repeated in the absence or presence of the membrane stabilizing agent pluronic F-68 or foetal calf serum (FCS). Third, quiescent myocytes were incubated at room temp with normal Tyrode solution (with and without FCS) in the absence or presence of H3. Cell viability was measured after 5 and 60 min. RESULTS: In 33 out of 34 electrically stimulated myocytes, exposure to H3 induced Ca2+ overload and spontaneous contractions within 8 min. In 13 out of 22 stimulated myocytes, exposure to Hmix also induced arrhythmogenesis. Pluronic F-68 (100 mg/100 ml) offered no protection on exposure to H3 as 18 out of 18 myocytes were arrhythmic, whereas 5% FCS protected 10 out of 11 myocytes from arrhythmogenesis. For populations of quiescent myocytes, incubation with H3 led to a significant 27% reduction in cell viability (P<0.05) from 5 to 60 min, however the presence of 5% FCS protected against necrosis. CONCLUSION: H3 induced Ca2+ overload, arrhythmogenesis and cell death in ventricular myocytes. Pluronic F-68 failed to protect myocytes while FCS protected against cell necrosis, suggesting plasma proteins are potential cytoprotective agents against acute histone-induced cytotoxicity.