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The effects of tegaserod, a gastrokinetic agent, on voltage‐gated K + channels in rabbit coronary arterial smooth muscle cells
Author(s) -
An Jin Ryeol,
Jung Hee Seok,
Seo Mi Seon,
Kang Minji,
Heo Ryeon,
Park Hongzoo,
Song Geehyun,
Jung WonKyo,
Choi IlWhan,
Park Won Sun
Publication year - 2021
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.13477
Subject(s) - tegaserod , chemistry , pharmacology , biophysics , medicine , irritable bowel syndrome , biology
Tegaserod, a gastroprokinetic agent, is used to treat irritable bowel syndrome. Despite its extensive clinical use, little is known about the effects of tegaserod on vascular ion channels, especially K + channels. Therefore, we examined the effects of tegaserod on voltage‐gated K + (Kv) channels in rabbit coronary arterial smooth muscle cells using the whole‐cell patch‐clamp technique. Tegaserod inhibited Kv channels in a concentration‐dependent manner with an IC 50 value of 1.26 ± 0.31 µmol/L and Hill coefficient of 0.81 ± 0.10. Although tegaserod had no effect on the steady‐state activation curves of the Kv channels, the steady‐state inactivation curve was shifted toward a more negative potential. These results suggest that tegaserod inhibits Kv channels by influencing their voltage sensors. The recovery time constant of channel inactivation was extended in the presence of tegaserod. Furthermore, application of train steps (1 and 2 Hz) in the presence of tegaserod progressively increased the inhibition of Kv currents suggesting that tegaserod‐induced Kv channel inhibition is use (state)‐dependent. Pretreatment with a Kv1.5 subtype inhibitor suppressed the Kv current. However, additional application of tegaserod did not induce further inhibition. Pretreatment with a Kv2.1 or Kv7 inhibitor did not affect the inhibitory effect of tegaserod on Kv channels. Based on these results, we conclude that tegaserod inhibits vascular Kv channels in a concentration‐ and use (state)‐dependent manner independent of its own functions. Furthermore, the major Kv channel target of tegaserod is the Kv1.5 subtype.