Characterization of direct perturbations on voltage-gated sodium current by esaxerenone, a nonsteroidal mineralocorticoid receptor blocker

Esaxerenone (ESAX; CS-3150, Minnebro®) is known to be a newly non-steroidal min-eralocorticoid 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_Na ) identified from pituitary GH₃ or MMQ cells. GH₃-cell exposure to ESAX depressed the transient and late components of I_Na with varying potencies. The IC₅₀ value of ESAX required for its differential reduction in peak or late I_Na in GH₃ cells was estimated to be 13.2 or 3.2 µM, respectively. The steady-state activation curve of peak I_Na remained unchanged during exposure to ESAX; however, recovery of peak 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_Na . ESAX (3 µM) potently reversed Tef-induced augmentation of I_Na . By using isosceles-triangular ramp pulse with varying durations, the amplitude of persistent 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_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_Na in electrically excitable cells.