Hybridomas are fused immortal lymphocytes that typically secrete monoclonal antibodies to a known antigen. Hybridomas express two ionic conductances that have properties consistent with epithelial sodium channel (ENaC) and CFTR. Both ion channels are expressed by lymphocytes. Both of these channels are known to play a role in epithelial cell physiology. However, the physiological role of these channels in lymphocytes is unclear. We tested the hypothesis that ENaC plays a role in the process of regulated antibody secretion. We have been able to demonstrate that hybridomas can be provoked to acutely secrete monoclonal antibodies by a variety of agonists. Concurrently, we were able to show that these same agonists activate amiloride-sensitive sodium currents in whole cell clamped hybridomas. Inhibition of ENaC by amiloride inhibited the acute provoked antibody secretion, thereby linking ENaC to the process of acute antibody secretion. Interestingly, the concentration of amiloride necessary to completely inhibit the provoked secretion was approximately an order of magnitude higher than the concentration necessary to inhibit all of the transmembrane current. However, because amiloride is a weak base, the equilibrium concentration necessary to produce partial inhibition was precisely in accord with the K_i for amiloride and ENaC, indicating that the inhibition was intracellular.