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  • Title: The muscarinic receptor antagonist tolterodine inhibits voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells.
    Author: Seo MS, An JR, Jung HS, Jung WK, Choi IW, Na SH, Park H, Bae YM, Park WS.
    Journal: Eur J Pharmacol; 2020 Mar 05; 870():172921. PubMed ID: 31935397.
    Abstract:
    We explored the effect of the muscarinic receptor antagonist tolterodine on voltage-dependent K+ (Kv) channels using the patch-clamp technique in coronary arterial smooth muscle cells freshly isolated from rabbits. Tolterodine inhibited Kv channels in a concentration-dependent manner, with an IC50 of 1.71 ± 0.33 μM and Hill coefficient of 0.69 ± 0.03. Tolterodine accelerated the decay rate of Kv channel inactivation. The apparent rate constants of association and dissociation for tolterodine were 1.79 ± 0.13 μM-1s-1, and 3.13 ± 0.96 s-1, respectively. Although 3 μM tolterodine had no effect on the steady-state activation of the Kv current, it shifted the steady-state inactivation curve towards a negative potential. Application of consecutive train steps (1 or 2 Hz) progressively decreased the Kv current and promoted its inhibition. Furthermore, the recovery time constant was augmented in the presence of tolterodine, indicating that tolterodine-induced Kv channel blockade is use (state) dependent. Pretreatment with inhibitors of the Kv1.5, Kv2.1, and Kv7 subtypes (DPO-1, guangxitoxin, and linopirdine) partially reduced the inhibitory effect of tolterodine on Kv channels. The alternative muscarinic receptor antagonist atropine did not inhibit the Kv current nor influence tolterodine-induced inhibition of the Kv current. Tolterodine induced vasoconstriction and membrane depolarization. Based on these results, we conclude that tolterodine inhibits Kv channels in concentration-, time-, and use (state)-dependent manners, irrespective of its antagonism of muscarinic receptors.
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