The selective serotonin reuptake inhibitor dapoxetine inhibits voltage‐dependent K<sup>+</sup> channels in rabbit coronary arterial smooth muscle cells

Kim, Han Sol; Li, Hongliang; Kim, Hye Won; Shin, Seungjae; Jung, Won‐Kyo; Ha, Kwon‐Soo; Han, Eun‐Taek; Hong, Seok‐Ho; Firth, Amy L.; Choi, Il‐Whan; Park, Won Sun

doi:10.1111/1440-1681.12723

Cited by 10 publications

(1 citation statement)

References 32 publications

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“…Furthermore, several selective serotonin reuptake inhibitors have been reported to inhibit vascular Kv channels independently of serotonin reuptake inhibition. For example, dapoxetine inhibited the vascular Kv channel in a concentration‐, time‐, and (open) state‐dependent manner by shifting inactivation curves to a more negative potential 21 . Sertraline inhibited vascular Kv channels by shifting inactivation curves to a more negative potential 22 .…”

Section: Discussionmentioning

confidence: 99%

The effects of tegaserod, a gastrokinetic agent, on voltage‐gated K⁺ channels in rabbit coronary arterial smooth muscle cells

Jung

Seo

et al. 2021

Clin Exp Pharma Physio

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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 IC50 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.

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Section: Discussionmentioning

confidence: 99%

The effects of tegaserod, a gastrokinetic agent, on voltage‐gated K⁺ channels in rabbit coronary arterial smooth muscle cells

Jung

Seo

et al. 2021

Clin Exp Pharma Physio

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Multitargeting in cardioprotection: An example of biaromatic compounds

Mokrov

2023

Archiv der Pharmazie

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A multitarget drug design approach is actively developing in modern medicinal chemistry and pharmacology, especially with regard to multifactorial diseases such as cardiovascular diseases, cancer, and neurodegenerative diseases. A detailed study of many well‐known drugs developed within the single‐target approach also often reveals additional mechanisms of their real pharmacological action. One of the multitarget drug design approaches can be the identification of the basic pharmacophore models corresponding to a wide range of the required target ligands. Among such models in the group of cardioprotectors is the linked biaromatic system. This review develops the concept of a “basic pharmacophore” using the biaromatic pharmacophore of cardioprotectors as an example. It presents an analysis of possible biological targets for compounds corresponding to the biaromatic pharmacophore and an analysis of the spectrum of biological targets for the five most known and most studied cardioprotective drugs corresponding to this model, and their involvement in the biological effects of these drugs.

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Inhibition of the Voltage-Dependent K+ Current by the Tricyclic Antidepressant Desipramine in Rabbit Coronary Arterial Smooth Muscle Cells

Shin

et al. 2017

Cardiovasc Toxicol

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We describe the effect of a tricyclic antidepressant drug desipramine on voltage-dependent K (Kv) currents in freshly isolated rabbit coronary arterial smooth muscle cells using a conventional whole-cell patch clamp technique. Application of desipramine rapidly decreased the Kv current amplitude in a concentration-dependent manner, with an IC value of 5.91 ± 0.18 μM and a Hill coefficient of 0.61 ± 0.09. The steady-state inactivation curves of the Kv channels were not affected by desipramine. However, desipramine shifted the steady-state inactivation curves toward a more negative potential. Application of train pulses (1 or 2 Hz) slightly reduced the Kv current amplitude. Such reduction in the Kv current amplitude by train pulses increased in the presence of desipramine. Furthermore, the inactivation recovery time constant was also increased in the presence of desipramine, suggesting that desipramine-induced inhibition of the Kv current was use-dependent. Application of a Kv1.5 inhibitor (DPO-1) and/or a Kv2.1 inhibitor (guangxitoxin) did not change the inhibitory effect of desipramine on Kv currents. Based on these results, we concluded that desipramine directly inhibited the Kv channels in a dose- and state-dependent manner, but the effect was independent of norepinephrine/serotonin reuptake inhibition.

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The selective serotonin reuptake inhibitor dapoxetine inhibits voltage‐dependent K⁺ channels in rabbit coronary arterial smooth muscle cells

Cited by 10 publications

References 32 publications

The effects of tegaserod, a gastrokinetic agent, on voltage‐gated K⁺ channels in rabbit coronary arterial smooth muscle cells

The effects of tegaserod, a gastrokinetic agent, on voltage‐gated K⁺ channels in rabbit coronary arterial smooth muscle cells

Multitargeting in cardioprotection: An example of biaromatic compounds

Inhibition of the Voltage-Dependent K+ Current by the Tricyclic Antidepressant Desipramine in Rabbit Coronary Arterial Smooth Muscle Cells

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The selective serotonin reuptake inhibitor dapoxetine inhibits voltage‐dependent K+ channels in rabbit coronary arterial smooth muscle cells

Cited by 10 publications

References 32 publications

The effects of tegaserod, a gastrokinetic agent, on voltage‐gated K+ channels in rabbit coronary arterial smooth muscle cells

The effects of tegaserod, a gastrokinetic agent, on voltage‐gated K+ channels in rabbit coronary arterial smooth muscle cells

Multitargeting in cardioprotection: An example of biaromatic compounds

Inhibition of the Voltage-Dependent K+ Current by the Tricyclic Antidepressant Desipramine in Rabbit Coronary Arterial Smooth Muscle Cells

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The selective serotonin reuptake inhibitor dapoxetine inhibits voltage‐dependent K⁺ channels in rabbit coronary arterial smooth muscle cells

The effects of tegaserod, a gastrokinetic agent, on voltage‐gated K⁺ channels in rabbit coronary arterial smooth muscle cells

The effects of tegaserod, a gastrokinetic agent, on voltage‐gated K⁺ channels in rabbit coronary arterial smooth muscle cells