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)‐α and IL‐1β 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.