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Esaxerenone (ESAX; CS-3150, Minnebro^®) is known to be a newly non-steroidal mineralocorticoid receptor (MR) antagonist. However, its modulatory actions on different types of ionic currents in electrically excitable cells remain largely unanswered. The present investigations were undertaken to explore the possible perturbations of ESAX on the transient, late and persistent components of voltage-gated Na⁺ current (<i>I</i>_Na) identified from pituitary GH₃ or MMQ cells. GH₃-cell exposure to ESAX depressed the transient and late components of <i>I</i>_Na with varying potencies. The IC₅₀ value of ESAX required for its differential reduction in peak or late <i>I</i>_Na in GH₃ cells was estimated to be 13.2 or 3.2 μM, respectively. The steady-state activation curve of peak <i>I</i>_Na remained unchanged during exposure to ESAX; however, recovery of peak <i>I</i>_Na block was prolonged in the presence 3 μM ESAX. In continued presence of aldosterone (10 μM), further addition of 3 μM ESAX remained effective at inhibiting <i>I</i>_Na. ESAX (3 μM) potently reversed Tef-induced augmentation of <i>I</i>_Na. By using isosceles-triangular ramp pulse with varying durations, the amplitude of persistent <i>I</i>_Na measured at high or low threshold was enhanced by the presence of tefluthrin (Tef), in combination with the appearance of the figure-of-eight hysteretic loop; moreover, hysteretic strength of the current was attenuated by subsequent addition of ESAX. Likewise, in MMQ lactotrophs, the addition of ESAX also effectively decreased the peak amplitude of <i>I</i>_Na along with the increased current inactivation rate. Taken together, the present results provide a noticeable yet unidentified finding disclosing that, apart from its antagonistic effect on MR receptor, ESAX may directly and concertedly modify the amplitude, gating properties and hysteresis of <i>I</i>_Na in electrically excitable cells.