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  • Title: Inhibitory effect of immunosuppressive drug tacrolimus on voltage-gated K+ current in rabbit coronary arterial smooth muscle cells.
    Author: Li H, An JR, Seo MS, Ha KS, Han ET, Hong SH, Jung WK, Lee DS, Yim MJ, Choi G, Lee JM, Bae YM, Choi IW, Park WS.
    Journal: Eur J Pharmacol; 2019 Apr 15; 849():59-66. PubMed ID: 30716319.
    Abstract:
    In the present study, we investigated the inhibitory effect of tacrolimus, a macrolide immunosuppressive drug that acts through calcineurin inhibition, on voltage-gated K+ (Kv) channels expressed in native smooth muscle cells isolated from the coronary arteries of rabbits. Tacrolimus reduced the amplitude of Kv currents in a dose-dependent manner with an IC50 value and Hill coefficient of 7.80 ± 3.01 μM and 1.07 ± 0.25, respectively. Tacrolimus caused a shift in the activation curve toward a more positive potential and in the inactivation curve toward a more negative potential. Tacrolimus-induced inhibition of Kv current was increased by the application of train pulses (1 or 2 Hz). Furthermore, the recovery time constant of inactivation was extended in the presence of tacrolimus, suggesting that tacrolimus inhibited Kv channels in a use-dependent manner. Two kinds of Kv subtype inhibitors, DPO-1 and guangxitoxin did not affect the degree of tacrolimus-induced inhibition of Kv current. Furthermore, pretreatment with another calcineurin inhibitor, cyclosporine A, did not affect the Kv current, and did not alter the inhibitory effect of tacrolimus. Using perforated-patch clamp experiments, inhibition of Kv channels by tacrolimus caused membrane depolarization. From these results, we concluded that tacrolimus inhibited the vascular Kv currents in a dose, state (open and closed)-dependent manner.
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