Amphibian tissues have been widely utilized for investigations involving vectorial ion transport, particularly the transport associated with the renal principal cell type. With the isolation of high resistance mammalian principal cell lines, it is useful to compare physiological responses to hormonal stimuli in mammalian lines with those previously obtained in the amphibian tissues. We have employed electrophysiological methods to compare the changes in short circuit current (I_SC) in response to vasotocin/vasopressin in the amphibian A6 Xenopus laevis kidney cell line and the mammalian cell line, mpkCCD_cl4 (mouse principal cells of the kidney cortical collecting duct). We have confirmed a natriferic (Na⁺ retaining) response mediated via the epithelial Na⁺ channel (ENaC) in both tissues manifested with similar dose response relationships. Our data also suggest that there is an anion secretory event that is involved in the stimulatory response to AVT/AVP in the A6 and mpkCCD_cl4 cell lines, although the time-course of this response demonstrates species differences. Thus, the responses to these peptide hormones are complex and have been remarkably conserved during evolution. We would like to sincerely thank Dr. Alain Vandewalle (INSERM U478, Paris, France) for providing the mpkCCD_cl4 cell line.