Trauma causes immediate cytokine release and the systemic inflammatory response syndrome (SIRS), often preceding sepsis and septic shock. Mechanisms may involve P2X7 ion channel activation via adenosine 5'-triphosphate (ATP) released from surrounding tissue and platelets. A number of single nucleotide polymorphisms (SNPs) influence the nature and magnitude of P2X7-stimulated cytokine release and apoptosis. In whole blood and isolated mononuclear blood cells (PBMCs) of donors with wild-type and heterozygous mutated genotypes, we found downregulated IL-8 and caspase-3 activation but no reproducible effect on tumor necrosis factor (TNF)-alpha and IL-1beta release. IL-8 and caspase-3 activation were both influenced by paxilline, an inhibitor of calcium-activated potassium channels. Confocal laser scanning microscopy demonstrated that calcium signaling is affected by paxilline as well. We propose that blockade of potassium channels may be relevant to attenuate ATP-induced cytokine responses and apoptosis. The presence of functional SNPs in heterozygous genotypes appears to play a role.